Click on the links below to access all the ArticlePlus for this article.
Please note that ArticlePlus files may launch a viewer application outside of your web browser.
Haemophilus influenzae type b (Hib) conjugate vaccines became available during 1987 and industrialized nations quickly introduced universal infant Hib vaccination with a near disappearance of invasive disease.1–3 Hib vaccine price remains relatively high, though, and in Asia meningitis surveillance studies have found low disease incidence,4–6 leading most countries in the region to choose not to introduce Hib vaccine. The World Health Organization (WHO) issued an updated position article on Hib vaccine in November 2006, stating that “in view of their demonstrated safety and efficacy, conjugate Hib vaccines should be included in all routine infant immunization programs.”7 Beginning during 2002 with assistance from the Global Alliance for Vaccines and Immunizations (GAVI), a number of low-income countries have now introduced Hib vaccine. However, many countries in Asia, including Indonesia, have not yet implemented current WHO recommendations.
A hamlet-randomized, double-blind Hib conjugate vaccine-probe study was undertaken on Lombok Island, Indonesia, during 1998–2002 to estimate Hib vaccine-preventable disease incidences for meningitis and pneumonia.8 Half of 55,073 enrolled children received diphtheria-tetanus-pertussis (DTP) + Hib vaccine and the other half DTP alone. Together with disease surveillance, treatment cost data were collected from a selection of health facilities included in the study. We conducted a cost-effectiveness analysis of routine infant Hib vaccination by combining the probe study effectiveness results with the treatment cost data and estimates of Hib vaccine delivery costs.
MATERIALS AND METHODS
We sought to estimate overall Hib disease burden and the costs per case, death, and disability adjusted life-year (DALY) averted from introducing Hib vaccine into routine infant immunization services in Indonesia. The analysis was carried out from a governmental and a societal perspective. A static model was developed to follow the 2007 Indonesian birth cohort until death. Two scenarios were constructed: one with Hib vaccine in routine immunization services and one without.
When available and justified, we used data from the Lombok probe study as representative of all of Indonesia. However, because Lombok differs from the average Indonesian situation in important areas, some indices required adjustment (as detailed further below). During 2005, Nusa Tenggara Barat province (which includes Lombok) had a population density of 216/km2 (116/km2 for Indonesia as a whole), an adult female literacy of 71% (the second lowest in Indonesia and compared with 87% for the country as a whole), a fertility rate of 2.5 (2.1 for Indonesia as a whole), and a mortality rate among children younger than 5 years of 103 per 1000 live births (the highest in the country and compared with 46 for Indonesia as a whole).9
The average 2007 exchange rate of US$1 to $9059 Indonesian rupiah was used in all calculations (www.oanda.com, last accessed August 15, 2007), and future costs and outcomes were discounted at 3% per year.10 Because Hib vaccine has an excellent safety record,7 we did not include costs of potential adverse events.
Probe Study Estimation of Disease Impact From Hib Vaccination.
The primary probe study end point was radiologically confirmed pneumonia (ie, an obvious alveolar infiltrate or pleural effusion), as defined by the WHO Radiology Working Group.11 Other pneumonia outcomes included any infiltrate on chest radiography, WHO-defined severe pneumonia with hospitalization, any severe pneumonia, and clinical pneumonia (ie, any WHO-defined acute lower respiratory tract infection).12 Meningitis outcomes were microbiologically confirmed Hib meningitis, WHO-defined probable bacterial meningitis,13 and clinical meningitis, defined as an admission for suspected acute bacterial meningitis or outpatient visit for fever and seizures.8 The vaccine-preventable disease burden was calculated as the difference in incidence between unvaccinated and vaccinated children for outcomes of interest. For children accessing health care facilities, these values provided a direct estimate of the measurable disease burden that infant Hib vaccination could prevent.
Adjustments to the Probe Study Disease Incidence Estimates.
Because surveillance was conducted in formal inpatient and outpatient health facilities during the probe study, disease incidence estimates did not include children experiencing meningitis and pneumonia that did not reach these facilities. We adjusted for limited access to care using data from the Indonesian 2002 Demographic and Health survey that estimated that 56.8% of children who showed symptoms of acute respiratory infection or fever received treatment at a health facility.9
The higher mortality rates among infants and children younger than 5 years found in Lombok compared with other areas of Indonesia suggest that data from Lombok will overestimate Hib case-fatality ratios and thus the total number of Hib-associated deaths. Consequently, we adjusted the number of Hib meningitis and pneumonia deaths downward by the ratio of the 2002 infant mortality rate in Indonesia (35 per 1000 live births) to that in Lombok (74 per 1000 live births).9
Finally, the probe study included only children less than 2 years of age. We used data from Bangladesh to predict the limited number of Hib cases occurring in children aged 3–5 years.14 We assumed that case-fatality ratios for children between 2 and 5 years of age were similar to those for children between 1 and 2 years of age. Values used for calculating the impact of Hib vaccine are summarized in Table 1 (available online only).
Although no published data address this issue, nonbacteremic and bacteremic Hib pneumonias may have a higher case-fatality ratio than all other pneumonias. By using the all-cause pneumonia case-fatality ratio, we may have underestimated the number of Hib pneumonia deaths. However, no data exist in the literature that compare case-fatality ratios for Hib pneumonia (including nonbacteremic) to other pneumonias. Consequently, we adjusted for this possibility by varying the case-fatality ratio during sensitivity analysis.
Disability Adjusted Life Years.
DALYs were estimated using standard methods, including age weighting.15 The average lengths of hospitalization observed during the probe study were used to approximate the duration of disability for acute episodes. For nonsevere pneumonia episodes we assumed a duration of disability of 3 days and for meningitis sequelae the remaining life time. Meningitis sequelae were divided into mental retardation, deafness, blindness, seizure disorder, and motor deficit,15 and different disability weights were applied to each category.16
Vaccine Delivery Costs.
Routine infant immunization in Indonesia includes Bacille Calmette-Guérin (BCG), oral polio, measles, DTP, and hepatitis B. In some parts of the country, children receive DTP and hepatitis B vaccines at 2, 3, and 4 months as a combined vaccine, whereas in others they receive separate injections. Since 2002 the GAVI has provided support to Indonesia for immunization services, safe injection equipment, and for the birth dose of hepatitis B vaccine delivered in a Uniject device.17 If the Indonesian government decides to apply to GAVI for Hib vaccine financing, the government would need to pay a fraction of total vaccine costs, at least $0.30 per dose during the first year with a 15% increase each year until 2015 (http://www.gavialliance.org/index.php).
We assessed 2 options for Hib vaccine introduction:
- Hib vaccine in monovalent form at 2, 3, and 4 months.
- DTP-Hepatitis B-Hib combined vaccine (pentavalent vaccine) at 2, 3, and 4 months.
Because pentavalent vaccine does not require any additional injections, health care workers and parents often prefer this presentation.18 However, Bio Farma, a state-owned vaccine manufacturer that supplies all vaccines to the Indonesian immunization program, does not currently produce Hib vaccine and it is uncertain when the company might develop this and in which presentation. Thus, the option of delivering monovalent Hib vaccine was also assessed. GAVI provides support for Hib vaccine in both pentavalent and monovalent presentation and the monovalent presentation would allow the Indonesian immunization program to continue use of Biopharma DTP and hepatitis B vaccines.
For the societal perspective, 2007 vaccine prices from UNICEF's (United Nations International Children's Emergency Fund) supply division were used: US$3.75 for liquid pentavalent vaccine and US$3 for Hib monovalent, freeze-dried vaccine (both in single dose vials).19 From the Government perspective, the GAVI Alliance cofinancing level of US$0.30 per dose for the first year was used. Injection equipment costs were collected from the Indonesian Ministry of Health. Other vaccine delivery costs—such as personnel time, storage, and vaccine transport—were not included.
Future Treatment Costs Saved.
To determine resource utilization, we retrospectively reviewed administrative hospital records of 174 pneumonia patients and 47 meningitis patients admitted during 2001–2002 to the urban Government hospital in Mataram (50% of the sample) and 2 rural Government hospitals. Data were collected on length of stay, drug use, emergency room care, laboratory tests, radiology evaluation, and medical specialist consultant visits.
Unit costs for hospital services were determined by reviewing accounts at the 3 study hospitals. Drug costs were estimated by conducting pricing surveys at the dispensaries used by the respective hospitals. Costs per outpatient visit were not available easily from Lombok, so we used the WHO estimate per visit for Indonesia.20 All unit costs were converted to 2007 US$ values using the Indonesian wholesale price index.21
To assess out-of-pocket costs, a pretested discharge questionnaire was administered to the families of 312 pneumonia patients and 66 meningitis patients admitted during October 2001 through September 2002. Out-of-pocket costs included payments or copayments for medical services before and during hospitalization (including traditional healers), transportation costs, and travel and lodging costs for family members during the child's hospitalization. For out-of-pocket costs after hospitalization we conducted interviews of only 22 patients (16 with pneumonia and 6 with meningitis), as we had limited access to patients postdischarge. We did not attempt to include the value of the time families spent providing care to ill children.
Some patients may have received additional medical services because of the presence of the probe study. We therefore collected resource utilization data for patients residing in both study and nonstudy villages and compared the cost estimates to identify any differences. However, as costs did not differ significantly, we did not distinguish between these categories in the analysis. Children from nonstudy villages represented 30–40% of the sample (depending on disease outcome) with the remainder from study villages.
Uncertainty and Sensitivity Analysis.
We conducted a probabilistic uncertainty analysis using ranges and assumed distributions of the uncertain variables to run a Monte Carlo simulation. Prediction intervals around the mean cost-effectiveness ratios were derived from 500,000 simulations using Crystal Ball software (Decisioneering Inc, Denver, CO). For the disease burden parameters we assumed a triangular distribution with minimum and maximum values (Table 1, online). Based on previous patterns22 and the treatment cost analysis of patient records, a lognormal distribution was assumed for the treatment cost parameters.
The Johns Hopkins Bloomberg School of Public Health Institutional Review Board and the National Institutes of Health Research and Development Ethical Commission of the Indonesian Ministry of Health approved all components of the Lombok study, including the cost study.
Impact of Hib Vaccine on Disease Incidence.
Among children aged less than 5 years, disease incidences per 100,000 child-years of follow-up without and with Hib vaccine were estimated as 509 and 395 for clinical meningitis (vaccine-preventable Hib meningitis incidence = 115); 3283 and 3157 for severe pneumonia (vaccine-preventable severe Hib pneumonia incidence = 126); and 25,435 and 24,426 for nonsevere pneumonia (vaccine-preventable nonsevere Hib pneumonia incidence = 1009).
Based on these results, we estimated that without Hib vaccine the 2007 Indonesian birth cohort of 4.2 million children would experience during the first 5 years of life 5,674,350 pneumonia episodes of all etiologies, 683,068 severe pneumonia episodes, and 105,983 episodes of clinical meningitis. Hib vaccine would prevent 210,000 (4.0%) nonsevere pneumonias, 26,156 (3.8%) severe pneumonias, and 23,888 (23%) clinical meningitis cases. Thus, without vaccine and during the first 5 years of life, 1 in every 20, 1 in every 163, and 1 in every 179 children would experience nonsevere Hib pneumonia, severe Hib pneumonia, and Hib clinical meningitis preventable by Hib vaccine, respectively.
Without vaccine and during the first 5 years of life, the 2007 birth cohort would experience 103,407 pneumonia deaths and 15,563 clinical meningitis deaths, of which Hib vaccine would prevent 4013 (3.9%) and 3513 (23%), respectively. In total, without vaccine, Hib will cause 1.8 deaths per 1000 children during their first 5 years of life. This equates to 4.9% of the 2005 mortality ratio among Indonesian children younger than 5 years of 36 per 1000 live births.23
Vaccine Delivery Costs.
From the societal perspective, the incremental costs of introducing pentavalent and monovalent vaccines were US$29.7 and US$39.1 million, respectively (Table 2). These values represent a 75% and 98% increase in total vaccine and injection costs to the Indonesian infant immunization program. Costs per fully vaccinated child were US$11.95 without Hib vaccine, US$20.88 with pentavalent vaccine (incremental cost US$8.93) and US$23.69 with monovalent Hib vaccine (incremental cost US$11.74).
With GAVI support and US$0.30 in cofinancing per dose, introduction of pentavalent vaccine will result in a decrease in vaccine and injection equipment costs from the perspective of the Indonesian Government. As seen in Table 2, costs will decrease by approximately 32%. If the monovalent Hib vaccine is introduced costs will increase by 9%.
Future Treatment Costs Saved.
The mean hospital stay was 6.4 days (SD: 2.9) for pneumonia and 8.1 days (SD: 6.4) for meningitis episodes. The total average societal costs for meningitis and pneumonia cases amounted to $239 and $189, respectively, per episode (Table 3, available online only). On average, out-of-pocket costs amounted to 30% and 28% of total costs for meningitis and pneumonia, respectively. As expected, all cost items had a relatively large standard deviation, reflecting the differences in disease severity, medical interventions, and health care seeking behavior of individual patients. Based on Lombok hospitalization rates during 1998–2002, we estimated that during the first 5 years of life for the 2007 Indonesian birth cohort, Hib vaccine would decrease societal expenditures for pneumonia and meningitis treatment by US$4.2 million and US$1.8 million, respectively. This is equivalent to 20% of the incremental costs of introducing pentavalent vaccine. From the Government viewpoint, the respective numbers are US$3.1 million and US$1.3 million.
From the societal viewpoint, net costs from introducing pentavalent vaccine amounted to US$23.9 million per year and the discounted costs per death and DALY averted amounted to US$3192 and US$74, respectively (Table 4, available online only). Similar results for the monovalent vaccine were US$4438 and US$102. From the Government viewpoint, resources worth approximately $17 million would be saved each year with the pentavalent and US$672,422 with the monovalent vaccine.
Sensitivity and Uncertainty Analysis.
Uncertainty analysis was conducted for the societal viewpoint analysis. The incremental costs per discounted DALY averted were less than US$204 with 90% certainty for pentavalent vaccine and less than US$282 for monovalent vaccine (Table 4, online). These are relatively wide confidence intervals and illustrate the impact of the substantial uncertainty in disease incidence estimates. Five of the 41 evaluated parameters contributed to 78% of the uncertainty in the result: severe pneumonia incidence (36%), meningitis incidence (14%), costs of hospital stay for pneumonia patients (11%), access to health care (10%), and nonsevere pneumonia case-fatality ratio (7%). Even though nonsevere pneumonias have a low associated mortality, the case-fatality ratio was important to the result because of the high vaccine-preventable incidence.
The price at which pentavalent vaccine would become cost-saving was US$1.75 per dose (Fig. 1). If, instead, treatment costs were increased and the vaccine price kept constant, Hib vaccine would become cost saving if treatment costs were 7 times higher than estimated in Lombok.
We estimate that Hib vaccine has the potential to prevent meningitis among 1 in every 179 children and pneumonia among 1 in every 18 children. Vaccine also could prevent approximately 4.9% of the current mortality among children under age 5 years in Indonesia. Few other available tested interventions have this potential to impact the United Nations Millennium Development Goal of reducing mortality among children younger than 5 years by 2015. During the base-case scenario and from the societal perspective, the cost-effectiveness of Hib vaccine amounted to US$74 per discounted DALY averted. WHO classifies interventions as “highly cost-effective” for a given country if they avert a DALY for less than the per capita gross national income (http://www.who.int/choice/costs/CER_thresholds/en/index.html). Based on a 2005 per capita gross national income of US$1280, Hib vaccination thus can be considered a highly cost-effective use of resources in Indonesia.
Few Hib vaccine cost-effectiveness studies from Asia exist,24,25 and no studies exist that incorporate disease burden derived from a probe study. The results from the current analysis are similar to those from other developing countries in that although the vaccine is cost-effective at current prices, routine infant immunization nevertheless requires a substantial yearly investment of resources from the societal perspective. A radically different situation exists in developed countries, however, with cost savings realized in excess of US$300 per child vaccinated.26,27 It is worth considering why Hib vaccination is cost-saving in developed countries but not in developing countries, such as Indonesia. In theory, development could lower Hib incidence by decreasing the prevalence of risk factors such as crowding. However, no evidence exists that Hib disease burden correlates with the wealth of the studied population.4 Instead, while case-fatality ratios may decrease with development,4 studies from developed countries indicate that the contribution of this factor to cost-effectiveness is overwhelmed by the contribution in the opposite direction from increases in acute and long-term treatment costs. In Indonesia, the total treatment cost for a case of hospitalized pneumonia was US$189 in 2007. In the United States this cost has been estimated as US$9274 in 2000,28 almost 50-fold higher. In addition, long-term care and special education for patients with sequelae contribute a major part of costs for Hib disease treatment in developed countries,27,28 costs not generally realized in rural Indonesia.
Because Indonesia has many pressing health care priorities and a limited budget, lower vaccine prices will likely increase vaccine use and financial sustainability in the short term. Nevertheless, over the long term as Indonesia further develops and treatment costs increase to values closer to those found in developed countries, vaccination will likely become cost saving even without substantial reductions in vaccine price. Until that happens, the low treatment costs in Indonesia and many other areas of the world argue that vaccination programs in developing countries should not be judged on their ability to provide cost savings.
The GAVI Alliance will provide cofinancing to Indonesia for Hib vaccine, requiring the Indonesian government to pay US$0.30 per dose during the first year of support and an incremental increase of 15% through at least 2015. At this vaccine cost, Hib vaccine in pentavalent and monovalent form will lead to cost savings from the government as well as from the societal perspective. Interventions that are cost saving should generally be adopted immediately, as limited health resources can be freed up for other use.
Our manuscript had several limitations. We did not include indirect costs such as parents not working to care for a child with short-term illness or chronic sequelae. Second, because of sample size limitations, the Lombok probe study could not directly estimate vaccine preventable Hib mortality. We did not include some costs and outcomes associated with Hib vaccine in a monovalent versus pentavalent presentation. These include storage facility and transport costs, potentially additional staff time, and adverse events related to additional injections. Although these costs and outcomes are likely to be minor, if added they would support further the relatively better cost-effectiveness of pentavalent vaccine.
The WHO recommends universal Hib vaccine implementation worldwide.7 The high absolute disease burden and cost-effectiveness of Hib vaccine provide moral and financial justification for introduction in Indonesia and the Indonesian Ministry of Health has elected to implement vaccine beginning during 2009. Rural Indonesia—represented by Lombok—is similar to many other poor and underdeveloped areas of Southeast Asia in terms of health care access and delivery, under 5 years of age acute respiratory illness burden, and infant mortality. Thus, universal infant Hib conjugate vaccine use is likely to be an appropriate intervention throughout the region.
The authors thank hundreds of people who contributed to this study from the Indonesian Ministry of Health, Jakarta, Indonesia; West Nusa Tenggara Provincial Government, Lombok, Indonesia; Mataram General Hospital, and District Hospitals in Praya and Selong, Lombok, Indonesia; Agence de Médecine Préventive, Paris, France; Program for Appropriate Technology in Health, Seattle, WA; Johns Hopkins University, Baltimore, MD; and Sanofi-Pasteur, Lyon, France.
1. Adams WG, Deaver KA, Cochi SL, et al. Decline of childhood Haemophilus influenzae
type b (Hib) disease in the Hib vaccine era. JAMA
2. Peltola H. H. influenzae
in the post-vaccination era. Lancet
3. Peltola H, Salo E, Saxen H. Incidence of Haemophilus influenzae
type b meningitis during 18 years of vaccine use: observational study using routine hospital data. BMJ
4. Bennett JV, Platonov AE, Slack MPE, Mala P, Burton AH, Roberson SE. Haemophilus influenzae Type b (Hib) Meningitis in the Pre-Vaccine Era: A Global Review of Incidence, Age Distributions, and Case-Fatality Rates. WHO/V&B/0218. Geneva: WHO; 2002.
5. Rerks-Ngarm S, Treleaven SC, Chunsuttiwat S, et al. Prospective population-based incidence of Haemophilus influenzae
type b meningitis in Thailand. Vaccine
6. Anh DD, Kilgore PE, Kennedy WA, et al. Haemophilus influenzae
type B meningitis among children in Hanoi, Vietnam: epidemiologic patterns and estimates of H. influenzae
type B disease burden. Am J Trop Med Hyg
7. World Health Organization. WHO position paper on Haemophilus influenzae
type b conjugate vaccines. Wkly Epidemiol Rec
8. Gessner BD, Sutanto A, Linehan M, et al. Incidences of vaccine-preventable Haemophilus influenzae
type b pneumonia and meningitis in Indonesian children: hamlet-randomised vaccine-probe trial. Lancet
9. Badan Pusat Statistik-Statistics Indonesia (BPS) and ORC Macro: Indonesia Demographic and Health Survey 2002–2003. Calverton, MD: BPS and ORC Macro; 2003.
10. Gold MR, Siegel JE, Russell LB, Milton CW. Cost-Effectiveness in Health and Medicine
. New York, NY: Oxford University Press; 1996.
11. Cherian T, Mulholland EK, Carlin JB, et al. Standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies. Bull World Health Organ
12. World Health Organization. Technical Bases for the WHO Recommendations on the Management of Pneumonia in Children at First-Level Health Facilities
. Geneva: Programme for the Control of Acute Respiratory Infections WHO; 1991.
13. World Health Organization. Generic Protocol for Population-Based Surveillance of Haemophilus influenzae Type b
. Global Programme for Vaccines and Immunization, Vaccine Research and Development WHO/VRD/GEN/95;05; 1995.
14. Saha SK, Baqui AH, Darmstadt GL, et al. Invasive Haemophilus influenzae
type B diseases in Bangladesh, with increased resistance to antibiotics. J Pediatr
15. Goetghebuer T, West TE, Wermenbol V, et al. Outcome of meningitis caused by Streptococcus pneumoniae
and Haemophilus influenzae
type b in children in The Gambia. Trop Med Int Health
16. Murray CJL, Lopez ADE. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability From Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Boston, MA: Harvard School of Public Health; 1996.
17. Government of Indonesia. Progress report to the Global Alliance for Vaccines and Immunization (GAVI) and The Vaccine Fund by the Government of Indonesia Jakarta. Government of Indonesia; 2004.
18. Decker MD. Principles of pediatric combination vaccines and practical issues related to use in clinical practice. Pediatr Infect Dis J
19. Product menu for vaccines supplied by Unicef for the Global Alliance for Vaccines and Immunization (GAVI). Available at: http://www.unicef.org/supply/files/UNICEF_-_Procuring_supplies_for_children_-_GAVI.pdf
. Accessed September 20, 2007.
20. World Health Organization. Estimates of Unit Costs for Patient Services for Indonesia
. Geneva: WHO; 2007.
21. Asian Development Bank. Key indicators 2006: measuring policy effectiveness in health and education. Manilla: Asian Development Bank; 2006. Available at: http://www.adb.org/documents/books/key_indicators/2006/default.asp
. Accessed March 21, 2008.
22. Heyse JF, Cook JR, Carides GW. Statistical considerations in analysing health care resource utilization and cost data. In: Drummond M, McGuire A, eds. Economic Evaluation in Health Care: Merging Theory with Practice
. Oxford, UK: Oxford University Press; 2001:215–235.
23. World Bank. World Development Indicators
. World Bank; 2007.
24. Limcangco MR, Armour CL, Salole EG, Taylor SJ. Cost-benefit analysis of a Haemophilus influenzae
type b meningitis prevention programme in The Philippines. Pharmacoeconomics
25. Hussain IHM, Aljunid S, Sofiah A, et al. Cost-benefit analysis of Haemophilus influenzae
vaccination programme in Malaysia. Bull Kesihatan Masyarakat Jilid
26. Pokorn M, Kopac S, Neubauer D, Cizman M. Economic evaluation of Haemophilus influenzae
type b vaccination in Slovenia. Vaccine
27. Garpenholt O, Silfverdal SA, Levin LA. Economic evaluation of general childhood vaccination against Haemophilus influenzae
type b in Sweden. Scand J Infect Dis
28. Zhou F, Bisgard KM, Yusuf HR, Deuson RR, Bath SK, Murphy TV. Impact of universal Haemophilus influenzae
type b vaccination starting at 2 months of age in the United States: an economic analysis. Pediatrics