INVESTIGACIÓN ORIGINAL ORIGINAL RESEARCH

Potential cost-effectiveness of vaccination for rotavirus gastroenteritis in eight Latin American and Caribbean countries

Efectividad potencial en función del costo de la vacunación contra la gastroenteritis por rotavirus en ocho países de América Latina y el Caribe

Richard D. RheingansI, *; Dagna ConstenlaI; Lynn AntilI; Bruce L. InnisII; Thomas BreuerIII

IDepartment of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America
IIGlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
IIIGlaxoSmithKline Biologicals, Rixensart, Belgium

ABSTRACT

OBJECTIVES: To estimate the costs, benefits and cost-effectiveness of vaccination for rotavirus gastroenteritis in eight Latin American and Caribbean countries: Argentina, Brazil, Chile, the Dominican Republic, Honduras, Mexico, Panama, and Venezuela.
METHODS: An economic model was constructed to estimate the cost-effectiveness of vaccination from the health care system perspective, using national administrative and published epidemiological evidence, country-specific cost estimates, and vaccine efficacy data. The model was applied to the first five years of life for the 2003 birth cohort in each country. The main health outcome was the disability-adjusted life year (DALY), and the main summary measure was the incremental cost per DALY averted. A 3% discount rate was used for all predicted costs and benefits. Sensitivity analyses evaluated the impact of uncertainty regarding key variables on cost-effectiveness estimates.
RESULTS: According to the estimates obtained with the economic model, vaccination would prevent more than 65% of the medical visits, deaths, and treatment costs associated with rotavirus gastroenteritis in the eight countries analyzed here. At a cost of US$24 per course (for a two-dose vaccine), the incremental cost-effectiveness ratio ranged from US$ 269/DALY in Honduras to US$10 656/DALY in Chile. Cost-effectiveness ratios were sensitive to assumptions about vaccine price, mortality, and vaccine efficacy. CONCLUSIONS: Vaccination would effectively reduce the disease burden and health care costs of rotavirus gastroenteritis in the Latin American and Caribbean countries analyzed here. From the health care system perspective, universal vaccination of infants is predicted to be cost-effective, based on current standards. Key words: Rotavirus; rotavirus vaccines; cost-benefit analysis; models, economic; Latin America; Caribbean Region. RESUMEN OBJETIVOS: Estimar los costos, los beneficios y la efectividad en función del costo de la vacunación contra la gastroenteritis por rotavirus en ocho países de América Latina y el Caribe: Argentina, Brasil, Chile, Honduras, México, Panamá, República Dominicana y Venezuela. MÉTODOS: Se elaboró un modelo económico para estimar la efectividad en función del costo de la vacunación, desde la perspectiva del sistema de salud, a partir de las constancias epidemiológicas nacionales oficiales y publicadas, los estimados de costos específicos de cada país y los datos de eficacia de la vacuna. El modelo se aplicó a los primeros cinco años de vida de la cohorte de nacidos en 2003 en cada uno de esos países. La principal medida de salud fueron los años de vida ajustados por discapacidad (AVAD) y la principal medida sintética fue el costo incremental por AVAD evitado. Se empleó una tasa de descuento de 3% para el pronóstico de los costos y beneficios. El impacto de la incertidumbre relacionada con las variables clave sobre la efectividad en función del costo se realizó mediante el análisis de sensibilidad. RESULTADOS: Según los estimados obtenidos mediante el modelo económico, la vacunación podría evitar más de 65% de las consultas médicas, de las muertes y del costo de tratamiento asociados con la gastroenteritis por rotavirus en los ocho países analizados. Con un costo total de US$ 24,00 (por las dos dosis de la vacuna), la razón incremental de la efectividad en función del costo varió entre US$269/AVAD en Honduras y US$ 10 656/AVAD en Chile. Las razones de la efectividad en función del costo fueron sensibles a las diversas hipótesis sobre el precio de la vacuna, la mortalidad y la eficacia de la vacuna.
CONCLUSIONES: La vacunación permitiría reducir eficazmente la carga de morbilidad y los costos de la atención sanitaria de la gastroenteritis por rotavirus en los países analizados de América Latina y el Caribe. Desde la perspectiva de los sistemas de salud, se prevé que la vacunación universal de todos los niños será efectiva en función del costo, según los estándares vigentes en la actualidad.

Palabras clave: Rotavirus, vacunas contra rotavirus, análisis costo-beneficio, modelos económicos, América Latina, Región del Caribe.

Rotavirus infection, the single most important cause of gastroenteritis, leads to dehydration and death in small children in developed and developing countries (1, 2). Gastrointestinal infections in children have a wide range of impacts on their families and society, including increased medical expenditures, lost productivity, other costs to households for the care of children, and pain and suffering caused to children and their families. Universal vaccination of infants with an effective rotavirus vaccine would likely reduce the incidence of moderate and severe gastroenteritis, as well as its burden on families and society.

A previous study estimated that rotavirus gastroenteritis is responsible for more than 15 000 deaths in children under 5 years of age in Latin America (1). In addition, several studies in Latin America have documented that rotavirus gastroenteritis is a common cause of hospitalization in children under 5 years of age (17). Rotavirus has also been shown to generate substantial economic costs for the health care system and society as a whole (6, 8). Cost-effectiveness studies elsewhere suggest that vaccination may be a cost-effective strategy for reducing this health and economic burden (9, 10).

The main impact of rotavirus gastroenteritis is the morbidity and mortality it causes in children, and information on the economic burden of disease and the cost-effectiveness of vaccination can aid decisionmakers in choosing interventions to improve health. Effective vaccines are now available for preventing rotavirus gastroenteritis (11, 12), but investments in medical advances such as new vaccines compete against other interventions for health sector resources. Information about the cost-effectiveness of vaccination provides an estimate of the health benefits resulting from the investment in vaccination, and such estimates can then be compared to the potential benefits of other interventions.

The objective of this analysis is to provide an estimate of the cost-effectiveness of universal rotavirus vaccination in eight Latin American and Caribbean countries. The estimates were developed using a spreadsheet-based decision-analytic model populated with a combination of country-specific data and estimates extrapolated from other countries for which data were lacking. Simulation techniques were used to develop ranges for these estimates, and to identify key data needs. In order to characterize vaccination benefits, the model used secondary data on the efficacy of Rotarix (GlaxoSmithKline Biologicals, Rixensart, Belgium), a live attenuated monovalent human rotavirus vaccine administered orally to infants at 2 and 4 months of age (11).

METHODS

Model overview

A decision-analytic model was developed using Excel software to estimate the economic burden of rotavirus gastroenteritis and the cost-effectiveness of vaccination in eight countries: Argentina, Brazil, Chile, the Dominican Republic, Honduras, Mexico, Panama, and Venezuela. These countries were selected because they comprise a large proportion of the population in Latin America and the Caribbean, and the eight nations also represent varying geographic areas, health standards, and income levels. They were also part of a related project to characterize the economic burden of disease in representative Latin American countries (8). The model estimated the expected health outcomes and costs associated with rotavirus gastroenteritis, and the events and costs that might be averted with vaccination of an annual birth cohort of children during the first five years of their life in each country (8). The principal inputs in the model included epidemiological information on disease incidence, health care costs associated with different types of cases, and the effectiveness and cost of vaccination.

The validity of the model was tested in several ways. The initial model was reviewed by a group of external experts convened by the Centers for Disease Control and Prevention and the Rotavirus Vaccine Program in Geneva, Switzerland, in February 2004. The predictive validity was assessed through a structured comparison to an independent alternative rotavirus cost-effectiveness model at a second meeting held in March 2006. Internal validity was also checked by testing the results obtained when extreme values were used in the model.

The primary perspective for this analysis was the health care system, which we analyzed in terms of direct medical costs associated with medical treatment in formal inpatient and outpatient settings. Direct medical costs included the costs of diagnostic tests, medication, supplies, facilities, and personnel needed for treatment, but excluded costs such as nonmedical costs to households, costs of informal medical treatment, or productivity losses to caregivers. The main health outcome measure was the disability-adjusted life year (DALY). Rotavirus vaccination was compared to current practice (no universal vaccination and current use of oral rehydration therapy). All estimates were based on the expected events and costs for the 2003 annual birth cohort until 5 years of age. Estimates were expressed in 2003 US$. All future costs and DALY estimates were discounted at a rate of 3%. Rotavirus disease and economic burden For each country, the disease burden was estimated as the expected number of rotavirus-associated events (hospitalizations, outpatient visits, and deaths) during the first five years of life for the 2003 birth cohort. The risk of rotavirus-related hospitalization, outpatient visit, and death are based on the cumulative risk of each event due to acute gastroenteritis by the age of 5 years, and the proportion of these events attributed to rotavirus. A detailed explanation of the methods used to estimate disease burden can be found in Rheingans et al. (8). Estimates of the number of events were based on the size of the birth cohort and the estimated age distribution of each event. Disease burden was also estimated in terms of DALYs. This aggregate measure makes it possible to compare outcomes for other diseases and interventions by quantifying the years of life lost (YLLs) due to premature mortality, and the years lived with disability (YLDs) (13). The average country-specific life expectancies at birth and 1 year of age (14) were used to calculate YLLs. Only morbidity from disease severe enough to require medical care was considered to calculate YLDs. Estimates for years lived with disability were calculated with default disability weights from the Global Burden of Disease Study (13), the World Health Organization (WHO) guidelines for cost-effectiveness studies (15), and an estimated duration of illness of six days (16). For rotavirus gastroenteritis, the DALYs were almost entirely based on the YLLs because disability from rotavirus infections is usually brief. A discount rate of 3% and age weighting were included to ensure comparability (15). The economic burden of rotavirus gastroenteritis for each country was estimated by combining estimates of the number of each type of event with information on the costs associated with the event. Country-specific estimates of direct medical costs, nonmedical direct costs, and productivity losses were developed for hospital and outpatient rotavirus events. For a complete description of the methods used to calculate the economic burden, see Rheingans et al. (8). Vaccination effectiveness and costs Vaccine efficacy from clinical trials provides an upper-bound estimate of the potential effectiveness in real world situations. In order to estimate the effectiveness of vaccination, we also considered information on the expected coverage, timing of illness, and the effectiveness of vaccination against different outcomes. The temporal pattern of these parameters must be considered since vaccination can only affect events that would have occurred after the vaccine was received. A decision-analytic model was developed to combine information on disease burden, coverage, and effectiveness in a temporally explicit fashion. The age distribution of disease was estimated for each of the key rotavirus outcomes (death, hospitalization, and outpatient visits) on the basis of published studies (4, 5, 7, 1623). The estimated total number of events for the annual birth cohort was then divided into the following age categories: 02 months, 35 months, 68 months, 911 months, 1223 months, 2435 months, 3647 months, and 4859 months. Next, the model considered the expected immunization status of children in each age category. It was assumed that the timing of the two-dose rotavirus vaccine would correspond to the delivery of the first and second diphtheria, pertussis, and tetanus (DPT) doses at 2 and 4 months of age. In the baseline analysis, national coverage of rotavirus vaccination was based on DPT3 coverage at 1 year of age for the year 2003, which ranged from 65% in the Dominican Republic to 99% in Chile (24, 25). Because rotavirus vaccination would occur with DPT doses one and two, but standardized coverage data are available only for the third DPT dose, this approach may underestimate the proportion of children who would receive both rotavirus vaccine doses. In addition, it was assumed that all children would receive the vaccine at the recommended time. Information on the efficacy of the Rotarix two-dose vaccine against clinical trial endpoints was converted to efficacy against epidemiologically relevant outcomes. Ruiz-Palacios and colleagues reported the efficacy for hospitalization from severe rotavirus gastroenteritis as 85% during the first year (11). Efficacy against rotavirus gastroenteritis resulting in outpatient visits was estimated as the reported mean of the efficacy against severe (85%) (11) and any (70%) (26) rotavirus gastroenteritis. Clinical trial data in Latin America have shown that vaccine efficacy increases with disease severity (26), and it was assumed that efficacy against mortality would be the same as efficacy against hospitalization. For the baseline analysis it was further assumed that one dose of the vaccine would have the same effectiveness as a full course during the inter-dosing period, as demonstrated in a clinical trial in Latin America (27). The effectiveness of vaccination was estimated by following the 2003 birth cohort through the age periods identified above, to the age of 5 years. The predicted reduction in the number of hospitalizations, outpatient visits, and deaths during this period was estimated based on vaccine coverage and efficacy. Calculations of cost-effectiveness also require estimates of vaccination costs. For this analysis, these costs included the cost of administration, the price of the vaccine, the number of doses given (based on coverage level), and expected losses from waste (assumed to be 10%). Administrative costs consist of the cost of health personnel and training, cold chain maintenance, storage space, and public education. No costs for adverse events were included, since the safety profile of the vaccine is no different from that of a placebo (11, 27). The analysis assumed that the rotavirus vaccine would be administered along with the current Expanded Program on Immunization (EPI) vaccines; therefore, incremental administrative costs would be low. Earlier studies estimated the cost of immunization for current EPI vaccines (2831); however, there were no data on the incremental cost of adding a vaccine to the current EPI regimen. Based on the range of estimates in previous immunization cost studies and the assumption of low incremental costs, the model assumed an administration cost of US$ 1.00 per course. Given that the actual price was unknown, vaccine cost was assumed to be US$24 per course for the two-dose vaccine, and alternative values were used in the sensitivity analysis. Cost-effectiveness analysis The cost-effectiveness summary measure was the net cost per DALY averted (US$/DALY). All costs are reported in 2003 US$. From the health care system perspective, net costs are defined as the cost of vaccination (administration and vaccine itself) minus the averted medical costs. Averted DALYs were calculated as the difference between the health burden without vaccination and the health burden with vaccination. The incremental cost-effectiveness ratio (ICER) is the ratio of the net costs to the net health benefits (US$/DALY). This ratio represents the net investment required to avert one DALY; thus, a lower ICER implies greater cost-effectiveness. The net cost per death averted was also calculated.

Several standards can be used to determine whether an intervention is cost-effective in terms of US$/DALY. The appropriateness of the different approaches depends on the perspective of the decisionmaker. The results presented here for rotavirus vaccination are intended to estimate cost-effectiveness from the health care perspective. The World Health Report 2002 suggests that "very cost-effective interventions" are those that "avert each additional DALY at a cost less than GDP [gross domestic product] per capita." In addition, the WHO considers interventions with a cost-effectiveness ratio (US$/DALY) between one and three times the per capita GDP as cost-effective (32).

In addition to the ICER, break-even price was calculated as a secondary outcome measure. The break-even price for each country was calculated as the price per course for which the cost of vaccination (procurement and delivery) equaled the expected cost savings to the health care system.

Sensitivity and uncertainty analyses

The model described above required country-specific data on the epidemiology of the disease, the costs associated with different outcomes, and vaccine effectiveness. Although some of these data were available, the quality and relevance were limited for others. These data limitations create uncertainties regarding the final estimates of costs and cost-effectiveness. Two approaches were used to address this uncertainty: sensitivity and uncertainty analyses.

A one-way sensitivity analysis was conducted to assess the impact of changes in individual parameters on the ICER for each country, and to assess the robustness of the analysis. The variables included in this analysis were incidence of hospitalization, outpatient visits, and death from rotavirus gastroenteritis; costs associated with different events; vaccine efficacy; and vaccine price.

An uncertainty analysis was conducted to evaluate the overall impact of these uncertainties on quantitative estimates, and to assess the need for additional data collection. A Monte Carlo model was developed based on the model of rotavirus disease burden and vaccination cost-effectiveness described above. In Monte Carlo analysis, individual point estimates of parameters are replaced with distributions of potential values (33). In a series of iterations, individual values are randomly selected from each of the distributions, and the results are calculated and stored. The process is repeated for a large number of iterations (10 000 in this case). The final product is a distribution of potential outcomes that describe the likely range of actual expected results.

For national disease burden variables, distributions were used to characterize the cumulative incidence of illness outcomes (hospitalization, outpatient visits, and death) in each country, and the proportion of each outcome due to rotavirus. The distributions specified a range around the value chosen for the analysis, and described the likelihood that the value chosen was representative of the true population value. Wider distributions were used for countries for which the estimates were extrapolated from foreign data. For cost variables, distributions were based on the cost estimates presented in Rheingans et al. (8). For estimates of vaccine effectiveness, distributions were used for efficacy (in protecting against rotavirus hospitalization, outpatient visits, and mortality), based on the reported confidence intervals from clinical trials (11, 26). Distributions were also included for the reduction in efficacy from using only one dose, and the reduction in efficacy during subsequent seasons. Table 1 summarizes the best estimates and distributions used in the analysis, including location parameters.

Uncertainty limits (5% and 95%) were estimated for key output parameters, including vaccine benefit (costs and DALYs averted) and the incremental cost-effectiveness ratio. Uncertainty analysis was also used to estimate the likelihood that vaccination would result in different levels of cost-effectiveness. In addition, a contribution-to-variance analysis was conducted to determine the contribution of the individual input parameters to the ICER.

RESULTS

Vaccination benefits

Table 2 shows the expected rotavirus- associated events (deaths, hospitalizations, and outpatient visits) and associated medical costs, without and with vaccination. According to our model, vaccination of the entire 2003 birth cohort would prevent 68% of rotavirus deaths and 69% of the health care costs associated with treatment for rotavirus (Table 2 and Table 3). For the eight countries studied here, vaccination would prevent 3 435 deaths for the 2003 annual birth cohort that is vaccinated. In addition, vaccination would prevent US$43.4 million in health care treatment costs and an additional US$ 16.8 million in societal costs (including nonmedical direct costs and productivity losses).

Cost-effectiveness analysis

Table 3 shows the results of the cost-effectiveness analysis, and summarizes the estimated treatment costs, deaths, and DALYs that would be averted with vaccination in each country. The cost of vaccination (administrative and procurement) is shown for an assumed vaccine price of US$24 per course. The break-even prices, below which vaccination would be cost-saving from the health care system perspective, range from US$ 1.47 per course in the Dominican Republic to US$10.33 in Chile. The incremental cost-effectiveness ratio was calculated as the net cost of vaccination (from the health care system perspective) divided by the DALY averted. At the baseline price of US$ 24 per course for the two-dose regimen, the ICER ranged from US$269/DALY in Honduras to US$ 10 656/DALY in Chile. Cost-effectiveness was also expressed as cost per death averted, which ranged from US$8 972 per death averted in Honduras to US$ 422 497 per death averted in Chile.

Sensitivity and uncertainty analyses

Upper and lower uncertainty limits generated by the Monte Carlo analysis are shown in Table 3. These bounds provide an overall measure of the likely incremental cost-effectiveness, given uncertainty in the many input parameters. An alternative way to view these results is using "cost-acceptability" curves. The results in Figure 1 are based on the cumulative distribution of the estimated ICERs from the Monte Carlo analysis. For each country, Figure 1 shows the likelihood (vertical axis) that vaccination would have an ICER less than a specific US$/DALY level (horizontal axis). To estimate the likelihood that vaccination would meet the standard for "very cost-effective" (ICER < per capita GDP) in a given country, a vertical line should be extrapolated from the horizontal axis at the country's per capita GDP to the curve for that country. The value on the vertical axis at this point would be the likelihood that the intervention meets this standard. For Mexico, for example, the vertical line would drawn at US$ 6 121, the per capita GDP for Mexico. Since the entire curve for Mexico is to the left of that vertical line, the likelihood that vaccination will be very cost-effective for Mexico (ICER < US$6 121/DALY) is more than 95%. For six of the eight countries, the likelihood that vaccination would be considered very cost-effective was greater than 95%. In the two remaining countries, vaccination had a greater than 90% chance of being considered cost-effective based on the standard of ICER < three times the per capita GDP. The results of one-way sensitivity analyses are presented in Table 4, and show the effect of changes in individual input parameters on the ICER for vaccination at the baseline price of US$ 24 per course. In most countries, the ICER estimates were most sensitive to changes in assumptions regarding rotavirus mortality and vaccine efficacy against mortality. For example, a 20% change in rotavirus mortality rate resulted in a 15% to 25% change in the ICER for all eight countries. The ICER was also significantly affected by the vaccine price used in the analysis. At a price of US$16 per course, the ICER ranged from US$ 161/DALY to US$4 437/DALY. The contribution-to-variance analysis revealed the proportion of variance in the estimated ICER at US$ 24/ course that was attributable to each of the input variables. In all countries, the primary sources of uncertainty in ICER estimates were overall diarrheal mortality, accounting for 15% to 22%; the proportion of diarrheal mortality attributable to rotavirus, accounting for 19% to 39%; and vaccine efficacy against mortality, accounting for 20% to 36%. Uncertainty in the direct costs of rotavirus hospitalization and outpatient visits accounted for 1% or less of the variance in all countries except Chile, where the costs of hospitalization and outpatient visits accounted for 17% and 2% of the uncertainty in the estimated ICER, respectively.

DISCUSSION

Benefits of vaccination

The results demonstrate that the incorporation of a rotavirus vaccine into routine vaccination schedules could effectively reduce the health and economic burden associated with rotavirus gastroenteritis in the eight countries analyzed here. In terms of effectiveness, it is estimated that introduction of a vaccination program would reduce mortality and the medical costs associated with treating illness by 67% to 72%. These benefits would be greatest in countries with the highest disease burden and the highest vaccine coverage rates. Although vaccine efficacy against mortality was assumed to be the same as for hospitalized cases (85%), the true efficacy (and, as a result, effectiveness) against mortality is unknown. Because the estimates suggest that vaccine efficacy would increase with increasing severity of illness (11), the assumption of equal vaccine efficacy against mortality appeared justified, and was explored further in the sensitivity analysis.

Economic evaluation of vaccination

From the health care system perspective, health interventions that result in negative net costs are excellent investments since they result in both improved health and cost savings. In practice, very few interventions meet this standard of cost savings (see Table 5). The analysis presented here suggests that although rotavirus vaccination would not be cost-saving in the countries studied, it would be very cost-effective, or at least cost-effective.

The cost-effectiveness analysis compared the net health care costs to the improvement in health, expressed as the ICER. The interpretation of whether an intervention is cost-effective depends on the ICER and the standard to which it is compared. The standard should reflect how much a decisionmaker is willing to invest to avert one DALY or to prevent one death. Sev-eral standards have been suggested "to determine whether an intervention is cost-effective. Using the World Health Report 2002 standard of cost-effectiveness (ICER < three times the per capita GDP) or very cost-effective interventions (ICER < per capita GDP), rotavirus vaccination at a vaccine price of US$24/course would be very cost-effective in six of the countries, and cost-effective in the two other countries analyzed here. Alternatively, national decisionmakers could compare the cost-effectiveness of rotavirus vaccination in their country to the cost-effectiveness of other health interventions being considered, including other strategies for diarrheal prevention, child nutrition, and immunization. Ideally, the most cost-effective intervention would be chosen first. Unfortunately, country-specific information is often unavailable and incomplete. The WHO-CHOICE project provides cost-effectiveness estimates of diarrheal prevention interventions by region (34). For developing countries in the Region of the Americas, the cost-effectiveness ratio for point-of-use water treatment and expansion of oral rehydration therapy are approximately US$ 1 000/DALY (34). Although this estimate may not be applicable for higher-income countries, the cost-effectiveness of rotavirus vaccination is comparable to this standard for most of the countries analyzed here. For purposes of comparison, additional cost-effectiveness ratios for other health interventions are shown in Table 5. However, caution should be used when comparing across studies, since there may be differences in the currency base year and in analytical assumptions. Ideally, vaccination should be compared to country-specific analyses of the cost-effectiveness of alternative health investments being considered in that country, assuming that the studies use similar methods.

Although a given intervention may be considered highly cost-effective, it may not be affordable because of national financial constraints. In this situation, the WHO World Health Report 2002 suggests that external resources should be made available for the investment (32). The results presented here demonstrate that vaccination would prevent substantial costs associated with rotavirus gastroenteritis. These averted treatment costs could partially offset the costs of vaccination.

Sensitivity and uncertainty analyses

In addition to providing an overall assessment of confidence in our estimates of economic burden and cost-effectiveness, the uncertainty analysis provides a method for identifying variables that were likely to significantly affect our final estimates of burden and cost-effectiveness. These variables should be targeted in future efforts to collect more precise country-specific estimates. Although improved estimates of rotavirus-associated mortality and vaccine efficacy against mortality would allow for more accurate estimates of vaccination cost-effectiveness, improved estimates of these parameters may be difficult to obtain. In spite of these data limitations, the uncertainty analysis showed that our estimates of cost-effectiveness were robust, and provided information that is potentially useful for decision-making.

Limitations of the study

The primary limitations of this study relate to the incompleteness of some epidemiological and vaccine effectiveness parameters identified in the uncertainty analysis, and the need to rely on secondary data. Although uncertainties in these parameters affect the estimated cost-effectiveness of vaccination, the magnitude of this impact was systematically assessed in the uncertainty and sensitivity analyses. The uncertainty analysis included those parameters that were expected to significantly influence cost-effectiveness; however, some factors were not considered. In particular, this analysis did not explicitly consider two factors that may impact the results of the study. First, delays in the timing of routine vaccinations might preclude the prevention of rotavirus-associated events occurring very early in childhood. Second, it is not known whether those children who are at the greatest risk of dying from rotavirus infection have the same vaccination coverage as the general population.

A final study limitation is that this analysis considered the direct effects of vaccination but did not consider the potential indirect protective effect of herd immunity for persons unprotected by the vaccine. Three groups of people could benefit if vaccination provided herd immunity: children prior to receiving the first dose of the vaccine, children who are not vaccinated, and children who are vaccinated but in whom immunization is unsuccessful. Unfortunately, there are no data on the magnitude of the herd immunity that might be conferred by partial penetration of vaccination in a population, although partial vaccination is a plausible scenario since children might be exposed to the vaccine strain shed by vaccinated children, and thus might be less exposed to the wild-type rotavirus. By analogy to other vaccine-preventable infectious diseases, the effect of herd immunity might be substantial, and might offset gaps in the delivery of full-course on-time vaccination. Therefore, herd immunity might contribute to the cost-effectiveness of rotavirus vaccination.

In conclusion, given the limits to financial resources available from national governments and donors, vaccination is potentially a cost-effective option for improving child health and reducing mortality in the Latin American and Caribbean countries analyzed here. The results of this study suggest that immunization of the entire annual birth cohort with an effective rota-virus vaccine could greatly reduce the disease burden and costs associated with rotavirus gastroenteritis. In addition, vaccination is a potentially cost-effective investment compared to other options to control childhood gastroenteritis across a range of vaccine prices.

Acknowledgments. Financial support for this project was provided by GlaxoSmithKline Biologicals. The authors would like to acknowledge the help of GSK Medical Advisors (salaried employees) for their valuable input in generating epidemiological data. The GSK Medical Advisors were: Yolanda Cervantes, GSK-Mexico; Marisol Navarrete, GSK-Chile; Eduardo Ortega, GSK-Caribbean and Central American Region; Pilar Rubio, GSK-Brazil; Ricardo Ruttiman, GSK-Argentina; José Tavares, GSK-Brazil; and Juan Pablo Yarzabal, GSK-Venezuela. We are indebted to Miguel O'Ryan, Maribel Rivera, Jorge Gómez, Irene Pérez-Schael, and Alexandre Linhares for their assistance with identifying epidemiological data and for their general support of the study. We also thank Ralf Clemens for reviewing the manuscript.

Note on conflict of interest. The Pan American Health Organization (PAHO) has purchased vaccines from GlaxoSmithKline, and PAHO has also received contributions from GlaxoSmithKline. While the Revista Panamericana de Salud Pública/Pan American Journal of Public Health is affiliated with PAHO, the Revista/Journal is an independent scientific publication whose articles do not necessarily reflect the opinions or official positions of PAHO on specific issues. The mention of particular companies or of certain manufacturers' products in the Revista/ Journal does not imply that they are endorsed or recommended by PAHO in preference to other ones of a similar nature. As with all other research articles published in the Revista/Journal, this article went through the regular process of peer review by outside experts.

REFERENCES

1.Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis. 2003;9(5):565_72.

2. O'Ryan M, Perez-Schael I, Mamani N, Pena A, Salinas B, Gonzalez G, et al. Rotavirus-associated medical visits and hospitalizations in South America: a prospective study at three large sentinel hospitals. Pediatr Infect Dis J. 2001;20(7):68593.

3. Linhares AC, Bresee JS. Rotavirus vaccines and vaccination in Latin America. Rev Panam Salud Publica. 2000;8(5):30531.

4. Pérez-Schael I, González R, Fernández R, Alfonzo E, Inaty D, Boher Y, et al. Epidemiological features of rotavirus infection in Caracas, Venezuela: implications for rotavirus immunization programs. J Med Virol. 1999;59(4): 5206.

5. Gomez JA, Sordo ME, Gentile A. Epidemiologic patterns of diarrheal disease in Argentina: estimation of rotavirus disease burden. Pediatr Infect Dis J. 2002;21(9):84350.

6. Ehrenkranz P, Lanata CF, Penny ME, Salazar-Lindo E, Glass RI. Rotavirus diarrhea disease burden in Peru: the need for a rotavirus vaccine and its potential cost savings. Rev Panam Salud Publica. 2001;10(4):2408.

7. Bok K, Castagnaro N, Borsa A, Nates S, Espul C, Fay O, et al. Surveillance for rotavirus in Argentina. J Med Virol. 2001;65(1):1908.

8. Rheingans RD, Constenla D, Antil L, Innis BL, Breuer T. Economic and health burden of rotavirus gastroenteritis for the 2003 birth cohort in eight Latin America and Caribbean countries. Rev Panam Salud Publica. 2007; 21(4):192_204.

9. Carlin JB, Jackson T, Lane L, Bishop RF, Barnes GL. Cost effectiveness of rotavirus vaccination in Australia. Aust N Z J Public Health. 1999;23(6):6116.

10. Tucker AW, Haddix AC, Bresee JS, Holman RC, Parashar UD, Glass RI. Cost-effectiveness analysis of a rotavirus immunization program for the United States. JAMA. 1998;279(17): 13716.

11. Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, Abate H, Breuer T, Clemens SC, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med. 2006;354(1):1122.

12. Vesikari T, Matson DO, Dennehy P, Van Damme P, Santosham M, Rodriguez Z, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006;354(1):2333.

13. Murray CJL, Lopez AD. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Cambridge: Harvard University Press; 1996.

14. World Health Organization, WHO Statistical Information System. Life tables for 191 countries. Geneva: WHO; 2001. Available from: http://www3.who.int/whosis/menu.cfm? path=whosis,bod,burden_statistics,life& language=english. Accessed 21 October 2004.

15. Baltussen R, Adam T, Tan Torres T, Hutubessy R, Acharya A, Evans D, et al. Generalized cost effectiveness analysis: a guide. Geneva: World Health Organization; 2002.

16. Liddle JL, Burgess MA, Gilbert GL, Hanson RM, McIntyre PB, Bishop RF, et al. Rotavirus gastroenteritis: impact on young children, their families and the health care system. Med J Aust. 1997;167(6):3047.

17. Velázquez FR, Matson DO, Guerrero ML, Shults J, Calva JJ, Morrow AL, et al. Serum antibody as a marker of protection against natural rotavirus infection and disease. J Infect Dis. 2000;182(6):16029.

18. González FS, Sordo ME, Rowensztein G, Sabbag L, Roussos A, De Petre E, et al. Diarrea por rotavirus: impacto en un hospital de niños de Buenos Aires. Medicina (B Aires). 1999; 59(4):3216.

19. Cardoso DD, Soares CM, Dias e Souza MB, de Azevedo MDS, Martins RM, Queiroz DA, et al. Epidemiological features of rotavirus infection in Goiânia, Goiás, Brazil, from 1986 to 2000. Mem Inst Oswaldo Cruz. 2003;98(1): 259.

20. Urrestarazu MI, Liprandi F, Pérez de Suárez E, González R, Pérez-Schael I. Características etiológicas, clínicas y sociodemográficas de la diarrea aguda en Venezuela. Rev Panam Salud Publica. 1999;6(3):14956.

21. Bok K, Castagnaro NC, Diaz NE, Borsa A, Cagnoli MR, Nates S, et al. Red de laboratorios de rotavirus: resultados del primer año de vigilancia. Rev Argent Microbiol. 1999; 31(1):112.

22. Barraza P, Avendaño LF, Spencer E, Calderón A, Prenzel I, Duarte E. Infección intrahospitilaria por rotavirus en lactantes, Santiago, Chile. Bol Oficina Sanit Panam. 1986;101(4): 32838.

23. Villa S, Guiscafré H, Martínez H, Muñoz O, Gutiérrez G. Seasonal diarrhoeal mortality among Mexican children. Bull World Health Organ. 1999;77(5):37580.

24. World Health Organization. WHO and UNICEF estimates of national immuniza- tion coverage. Geneva: WHO; 2003. Availa-ble from: http://www.who.int/vaccines surveillance/WHOUNICEF_Coverage_ Review/. Accessed 7 July 2004.

25. México, Consejo Nacional de Vacunación. Informes trimestrales de vacunación y vigilancia nutricional. Available from: http://www. conava.gob.mx. Accessed 3 November 2004.

26. De Vos B, Vesikari T, Linhares AC, Salinas B, Perez-Schael I, Ruiz-Palacios GM, et al. A rotavirus vaccine for prophylaxis of infants against rotavirus gastroenteritis. Pediatr Infect Dis J. 2004;23(10 Suppl):S17982.

27. Salinas B, Pérez-Schael I, Linhares A, Ruiz-Palacios G, Guerrero ML, Yarzabal JP, et al. Evaluation of safety, immunogenicity and efficacy of an attenuated rotavirus vaccine, RIX4414: a randomized, placebo-controlled trial in Latin American infants. Pediatr Infect Dis J. 2005;24(9):80716.

28. Brenzel L, Claquin P. Immunization programs and their costs. Soc Sci Med. 1994;39(4): 52736.

29. Miller MA, McCann L. Policy analysis of the use of hepatitis B, Haemophilus influenzae type b, Streptococcus pneumoniae-conjugate and rotavirus vaccines in national immunization schedules. Health Econ. 2000;9(1):1935.

30. Walker D, Mosqueira NR, Penny ME, Lanata CF, Clark AD, Sanderson CF, et al. Variation in the costs of delivering routine immunization services in Peru. Bull World Health Organ. 2004;82(9):676_82.

31. Waters HR, Dougherty L, Tegang SP, Tran N, Wiysonge CS, Long K, et al. Coverage and costs of childhood immunizations in Cameroon. Bull World Health Organ. 2004;82(9): 66875.

32. World Health Organization. Some strategies to reduce risk. In: WHO. World health report 2002: reducing risks, promoting healthy life. Geneva: WHO; 2002. Pp. 100144. Available from: http://www.who.int/whr/2002/en/. Accessed 14 December 2004.

33. Baltussen R, Hutubessy R, Evans D, Murray C. Uncertainty in cost-effectiveness analysis: probabilistic uncertainty analysis and stochastic league tables. Int J Technol Assess Health Care. 2002;18(1):1129.

34. World Health Organization. WHO-CHOICE cost-effectiveness analyses results. Geneva: WHO; 2000. Available from: http://www3. who.int/whosis/cea/cea_data.cfm?path= evidence,cea,cea_results&language=english. Accessed 23 January 2004.

35. Pan American Health Organization. Regional core health data systemtable generator 2004. Washington, D.C.: PAHO; 2004. Available from: http://www.paho.org/Project. asp?SEL=HD&LNG=ENG&ID=379. Accessed 6 August 2004.

36. Salinas B, Gonzalez G, Gonzalez R, Escalona M, Materan M, Schael IP. Epidemiologic and clinical characteristics of rotavirus disease during five years of surveillance in Venezuela. Pediatr Infect Dis J. 2004;23(10 Suppl): S1617.

37. Argentina, Ministerio de Salud y Ambiente de la Nación, Departamento Nacional de Estadísticas de Salud, Dirección de Estadísticas e Información de Salud. Egresos de establecimientos oficiales según variables seleccionadas. Buenos Aires: Ministerio de Salud y Ambiente; 2003.

38. Honduras, Secretaría de Salud, Departamento de Estadísticas. Informe de enfermedades transmisibles (TRANS). Tegucigalpa: Secretaría de Salud; 2002.

39. México, Instituto Mexicano del Seguro Social. Daños. In: Dirección de prestaciones médicas: información estadística en salud; 2002. Available from: http://www.imss.gob.mx/IMSS/ IMSS_SITIOS/DPM/. Accessed 25 January 2004.

40. México, Servicio Social de Salud, Dirección de Estadísticas e Información de Salud. Anuario estadístico 2000_2001. In: Sistema Nacional de Información en Salud; 20012002. Available from: http://www.salud.gob.mx/. Accessed 12 February 2004.

41. Brasil, Ministério da Saúde, Departamento de Informática do SUS. Morbidade hospitalar do SUS: diarréia e gastroenterite origem infecc presumív; 2002. Available from: http:// tabnet.datasus.gov.br/cgi/sih/mimap.htm. Accessed 20 September 2004.

42. Guardado JA, Clara WA, Turcios RM, Fuentes RA, Valencia D, Sandoval R, et al. Rotavirus in El Salvador: an outbreak, surveillance and estimates of disease burden, 2000_2002. Pediatr Infect Dis J. 2004;23(10 Suppl):S15660.

43. Weuthrich B, ed. Proceedings of the Sixth International Rotavirus Symposium. Washington, D.C.: Albert B. Sabin Vaccine Institute; 2005.

44. Carmona RC, Timenetsky Mdo C, da Silva FF, Granato CF. Characterization of rotavirus strains from hospitalized and outpatient children with acute diarrhoea in Sao Paulo, Brazil. J Med Virol. 2004;74(1):16672.

45. da Silva Domingues AL, da Silva Vaz MG, Moreno M, Camara FP. Molecular epidemiology of group A rotavirus causing acute diarrhea in infants and young children hospitalized in Rio de Janeiro, Brazil, 19951996. Braz J Infect Dis. 2000;4(3):11925.

46. Gusmão RH, Mascarenhas JD, Gabbay YB, Lins-Lainson Z, Ramos FL, Monteiro TA, et al. Rotavirus subgroups, G serotypes, and electrophoretypes in cases of nosocomial infantile diarrhoea in Belem, Brazil. J Trop Pediatr. 1999;45(2):816.

47. Linhares AC, Moncao HC, Gabbay YB, de Araujo VL, Serruya AC, Loureiro EC. Acute diarrhoea associated with rotavirus among children living in Belem, Brazil. Trans R Soc Trop Med Hyg. 1983;77(3):38490.

48. da Rosa e Silva ML, Naveca FG, Pires de Carvalho I. Epidemiological aspects of rotavirus infections in Minas Gerais, Brazil. Braz J Infect Dis. 2001;5(4):21522.

49. Coiro JR, Bendati MM, de Almeida Neto AJ, Heuser CF, Vasconcellos VL. Rotavirus infection in Brazilian children with acute enteritis: a seasonal variation study. Am J Trop Med Hyg. 1983;32(5):11868.

50. Cardoso DdD, Martins RM, Kitajima EW, Barbosa AJ, Camarota SC, Azevedo MS. Rotavirus e adenovirus em crianças de 05 anos hospitalizadas com ou sem gastrenterite em Goiânia-GO., Brasil. Rev Inst Med Trop Sao Paulo. 1992;34(5):4339.

51. Panamá, Ministerio de Salud, Departamento de Vigilancia de Factores Protectores y de Riesgos a la Salud y Enfermedad, Dirección de Epidemiología. Estadísticas de salud 2002. Panamá: MINSA; 2002.

52. Argentina, Ministerio de Salud. Boletín epidemiológico nacional. Buenos Aires: Ministerio de Salud; 2002.

53. Orlandi PP, Silva T, Magalhaes GF, Alves F, de Almeida Cunha RP, Durlacher R, et al. Enteropathogens associated with diarrheal disease in infants of poor urban areas of Porto Velho, Rondônia: a preliminary study. Mem Inst Oswaldo Cruz. 2001;96(5):6215.

54. Bittencourt JA, Arbo E, Malysz AS, Oravec R, Dias C. Seasonal and age distribution of rotavirus infection in Porto AlegreBrazil. Braz J Infect Dis. 2000;4(6):27983.

55. Stewien KE, da Cunha LC, Alvim Ade C, dos Reis Filho SA, Alvim MA, Brandão AA, et al. Rotavirus associated diarrhoea during infancy in the city of S. Luís (MA), Brazil: a two-year longitudinal study. Rev Inst Med Trop Sao Paulo. 1991;33(6):45964.

56. Teixeira JM, de Figueiredo RB, dos Santos HM, Ferreira MN, Camara GN. Aspectos epidemiológicos das infecções por rotavirus no Distrito Federal, Brasil. Rev Soc Bras Med Trop. 1991;24(4):22330.

57. Venezuela, Ministerio de Salud y Desarrollo Social, Dirección de Información Social y Estadística. Anuario de mortalidad 2001. Available from: http://www.msds.gov.ve/msds/ direcciones_msds/Epidemiologia/Estadistica/ Anuarios/Anuario01.pdf. Accessed 6 September 2004.

58. México, Secretaría de Salud, Sistema Nacional de Información en Salud. Principales causes de mortalidad infantil y edad preescolar 2002. Available from: http://www.salud.gob.mx/ apps/htdocs/estadisticas/mortalidad/ mortalidad.htm. Accessed 13 September 2004.

59. Brasil, Ministério da Saúde. Anuário estatístico de saúde do Brasil; 2001. Available from: www.datasus.gov.br. Accessed 6 September 2004.

60. Argentina, Ministerio de Salud. Agrupamiento de causas de mortalidad por división, político territorial de residencia, edad y sexo. Buenos Aires: Ministerio de Salud; 2002.

61. World Health Organization, WHO Statistical Information System. WHO mortality database. Available from: http://www3.who.int/ whosis/menu.cfm?path=whosis,mort& language=english. Accessed 1 June 2004.

62. Varley RC, Tarvid J, Chao DN. A reassessment of the cost-effectiveness of water and sanitation interventions in programmes for controlling childhood diarrhoea. Bull World Health Organ. 1998;76(6):61731.

63. Horton S, Sanghvi T, Phillips M, Fiedler J, Perez-Escamilla R, Lutter C, et al. Breastfeeding promotion and priority setting in health. Health Policy Plan. 1996;11(2):15668.

64. World Health Organization. List of Member States by WHO region and mortality stratum. Geneva: WHO; 2000. Available from: http:// www3.who.int/whosis/member_states/ member_states_stratum.cfm?path=evidence, cea,cea_regions,member_states_stratum. Accessed 18 January 2005.