Cost-effectiveness of universal pneumococcal vaccination for infants in Italy

Vaccine 23 (2005) 4565–4576

Cost-effectiveness of universal pneumococcal vaccination for infants in Italy M. Marchetti a,b,∗ , G.L. Colombo b a

Laboratory of Medical Epidemiology, IRCCS Policlinico San Matteo, viale Golgi 19, 27100 Pavia, Italy b S.A.V.E., via Previati 74, 20149 Milan, Italy Received 22 October 2004; received in revised form 20 April 2005; accepted 26 April 2005 Available online 23 May 2005

Abstract This study aimed at estimating the health and economic outcomes of universal infant vaccination with seven-valent pneumococcal conjugate vaccine (PCV-7) in Italy. A Markov model simulated lifetime evolution of a birth cohort (538,138 children): universal vaccination would avert 769 invasive infections, 18 deaths and 1323 life years. At base-case analysis, universal three-dose vaccination would cost D 26,449 (95% CI: D 1975–62,075) and D 38,286 (95% CI: 22,164–70,801) per life year-saved in the societal and the NHS perspective, respectively. In the hypothesis of a 5-year long protection period, vaccination would cost D 32,694 and D 43,115 per life-year saved. Considering yearly incidence of invasive pneumococcal disease reported for Veneto and Sardinia regions, PCV-7 vaccination would result highly cost-effective determining a cost of D 10,479 and D 16,890 per life year-save in the NHS and the societal perspective, respectively. © 2005 Elsevier Ltd. All rights reserved. Keywords: Pneumococcal conjugated vaccine; Cost-effectiveness analysis; Markov model

1. Introduction Infections due to Streptococcus pneumoniae or Pneumococcus sustain 23% of invasive diseases such as meningitis and bacteraemia [1]. S. Pneumoniae also causes about 30% of lower respiratory tract infections and 15% of acute otitis media in children [2]. Antibiotic therapy directed at clinical evident disease is becoming less and less powerful, due to an increasingly common penicillin-resistance of strains that sustain invasive pneumococcal disease (IPD) [3]: in Italy the prevalence of penicillin resistance is now 12–15% [4–7]. Higher frequencies of penicillin resistance, however, were found in South of Italy, and in samples from patients with meningitis than in non-meningitis IPD cases [4]. A conjugated 7-valent vaccine (PCV-7) has been developed and tested in two large and one small double-blind ran∗

Corresponding author. Tel.: +39 0382 503637; fax: +39 0382 503637. E-mail address: [email protected] (M. Marchetti).

0264-410X/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2005.04.033

domized trials [9–12] and in field phase IV studies [13–15]. The largest trial, the Kaiser Permanente Study, randomised 37,868 children younger than 2 years to receive either PCV-7 or placebo and reported a 89.1% protection rate for IPD, a 17.7% protection for pneumonia and a 6.4% efficacy rate in preventing otitis [9]. Therefore, PCV-7 succeeded in extending the efficacy of anti-pneumococcal vaccine to young children [8,9]. Moreover, infant vaccination reduced the number of visits to physicians due to otitis [9] and greatly reduced the frequency of infection-related hospitalisations [10]. The clinical effectiveness of PCV-7 was also confirmed by community studies that showed a wide reduction in the rate of IPD and otitis after the introduction of PCV-7 [14,15]. Moreover, infections sustained by penicillin-resistant strains, most of which are included in PCV-7 [16,17], decreased by 35% after the introduction of PCV-7 [14]. All these pieces of evidence supported the recommendation the American Academy of Paediatrics made to perform routine pneumococcal vaccination in infants below <24 months of age [18].

4566

M. Marchetti, G.L. Colombo / Vaccine 23 (2005) 4565–4576

Italy ranks last in Europe for vaccinations, so that the economic resources allocated towards vaccinations in our country do not even reach 5% of the total health expenditures [19]. Pneumococcal vaccination uptake in children actually is 0.5% [20] and universal infant vaccination for pneumococcus has not been funded in Italy, yet. Timely cost-effectiveness analysis can be used to guide decisions on reimbursement for new therapeutics or the introduction of new vaccines in existing immunization schedules [21]. We, therefore, undertook a study, using cost-effectiveness and decision analysis approaches, to compare the option of universal infant vaccination with no vaccination. This

study adopted both the government payer’s and the societal perspective in order to support policy making.

2. Methods 2.1. The model A decision-analytic model for a hypothetical birth cohort of 538,138 infants [24] was constructed using TreeAge Pro (TreeAge Software Inc., Williamstown, MA). The model compared the costs and survival of vaccination with

Fig. 1. Decision tree.

M. Marchetti, G.L. Colombo / Vaccine 23 (2005) 4565–4576

no vaccination (Fig. 1). Targeted vaccination of high-risk children is already in place in Italy, however, only a small portion of overall IPD cases incur in high-risk patients [20] and no data are available to compare universal vaccination to currently founded selected vaccination. The structure of the decision model is shown in Fig. 1a Markov tree allowed the members of the birth cohort to flow yearly through a tunnel state up to 14 years of age: during this time period they might experience IPD and possibly die of IPD, incur pneumonia or otitis or even die for other causes. While any two or all three of these illnesses may occur together, in the model individuals experiencing two or more illnesses were counted only for to the most serious one. In order of severity these are IPD followed by non-bacteremic pneumonia and by otitis media. Therefore, the probability of incurring otitis was the incidence-derived probability of the event minus the probability of incurring pneumonia or IPD. Events probabilities were estimated from incidence rates through an exponential transformation [23]: p = 1 − exp (−rt)

(1)

After the year 14, infections were not tracked anymore and only life expectancy was modelled. Mortality for all causes was from national mortality tables [24].

4567

Based upon the above estimate for incidence of pneumococcal meningitis and the proportion between pneumococcal meningitis and overall IPDs, we calculated the incidence rate of overall IPDs. Based upon hospital discharge data [28] and results of recent surveillance studies [30], we considered that the proportion of meningitis to overall IPDs was 28% of overall IPDs in infants and 10% in older children. Focal non-meningitis IPDs were assumed to be one fourth of overall IPDs, irrespectively of age [31]. The cumulative incidence of IPD in children aged less than 5 years resulted to be 120/100,000, which is similar or higher than data from France [32], Germany [33] and Switzerland [34]. However, recent prospective surveillance programs conducted in a Northern and a Southern Italian region provided yearly estimates of IPD incidence in children below 3–5 years of age that are far higher than the data above, i.e. 58.9/100.000/year [30]. Therefore, we strongly considered this issue at sensitivity analysis. Case fatality rate was 14.8% in 108 cases of pneumococcal meningitis, either adults or children, reported in Italy in the year 1994 [1,25]. In paediatric populations lower rates have been reported than in adults, but high fatality rates are reported in infants: a 14.3% rate was found in 46 children younger than 18 months [35]. Accordingly, we considered a higher fatality rate for children aged <2 years (Table 1) and lower rates for older children. Baseline values were consistent with national mortality data [24].

2.2. Disease parameters: IPD 2.3. Disease parameters: acute otitis media Italian data on the incidence of IPD are limited to meningitis [1,25,26]. However, incidence estimates provided by surveillance studies usually underestimate the real rates [27]. We, therefore, queried the national hospital discharge database for years 2000–2002 [28]. In children younger than 14 years, 265 hospitalizations were reported for ICD9-CM code 320.1 (pneumococcal meningitis) and 202 ones for ICD9-CM code 320.9 (non-specified non-viral meningitis). Recent data showed that 36% of cases with a “non-specified meningitis” discharge diagnosis are undiagnosed pneumococcal meningitis [29]. We, therefore, adjusted age-stratified discharge data for underdiagnosis bias. Incidence figures from surveillance studies were considered as the lower value of the range investigated by sensitivity analysis.

One thousand two hundred and thirty-five patients incurred yearly acute otitis media in an Italian cohort of 15,327 children followed for overall 5013 observation days [36]. The Italian figure is similar to the 22% yearly rate reported by Dutch General Practitioners (GPs) in children aged less than 10 years. However, the Dutch figure was considered an underestimation of true incidence rate, since only 30% of acute otitis are referred to GPs in that country [37]. In Italy most of the cases of acute otitis media are referred to the GP, therefore, we no not deem that the available Italian epidemiologic data can be affected by this bias. Nevertheless, the estimate of otitis incidence in Italy is lower than the figures for Australia (60% per-patient incidence in the first 2

Table 1 Baseline input data for PCV-7

Uptake Efficacy Efficacy Efficacy Side effects Direct cost Direct cost Direct cost Indirect cost Indirect cost a

Three doses IPD Otitis media (overall episodes) Pneumoniaa Fever over 39 ◦ C Vaccine (1 dose) Administration of vaccine (1 dose) Pediatrician visits for adverse effects (fever) Parents’ productivity loss for vaccination (4 h work) Parents’ productivity loss for a visit due to PCV-7 adverse effects (3 h work)

Clinical pneumonia with a positive chest X-ray film.

Baseline value

Range

Source

100% 89.1% 6.4% 17.7% 1%/dose D 39 D0 D 20,56 D0 D 39

82–100% 74–96% 3.9–8.7% 5–29% 0–2% D 15–80 D 0–10 D 10–30 D 0–52 D 0–39

[9,49] [9,14] [9,10] [54] [51] [76] Assumption [57] [59] Assumptions [60] [60]

4568

M. Marchetti, G.L. Colombo / Vaccine 23 (2005) 4565–4576

years of age) [31] and UK (49% yearly incidence in children younger than 10 years). Therefore, we investigated a wide range of otitis rate at sensitivity analysis. The incidence of otitis media declines with age [38,31], therefore we assumed that incidence over 5 years of age was half that reported for children 0–5 years of age. The average number of episode per children was reported to be 1.23 [36]: higher figures were reported in other countries and were used to build the upper boundary of the variable range [31,39]. 2.4. Disease parameters: pneumonia Thirty percent of pneumonia events in Italian children are sustained by Pneumococcus [40] and PCV-7 coverage in this setting is 16.8% [41].The available epidemiological data for Italy derive from the BOHEME study, which, however, incorporated pneumonia and bronco-pneumonia into a unique category and did not report specific outcomes for the subgroup receiving chest X-ray was applied [42]. Despite the very low hospitalisation rate for patients with pneumonia or broncopneumonia, i.e. 1.4% in the BOHEME study, we assumed that all the children with a chest X-ray-documented pneumonia would be hospitalised and discharged with a DRG code 91 (“pneumonia and pleuritis, age <18 years”). Therefore, we derived yearly incidence of pneumonia from the national database of hospital discharges, year 2002. Our assumption probably underestimated the real incidence of pneumonia, therefore, we investigated a wide range of values at sensitivity analysis. Pneumonia is associated with a case fatality rate of 0.3–0.4% [44], however, the present model assigned bacteremic pneumonia [46–48], which represents 1.6% of the cases [45], to the IPDs subgroup. Therefore, we assumed that no death occurred in children with non-bacteremic pneumonia. 2.5. Vaccine schedule, safety, coverage and efficacy Vaccination procedure used three doses of PCV-7 at 2, 4 and 6 months of age, as recently recommended (9 July 2004) by CDC in conjunction with the Advisory Committee on Immunization Practices (ACIP), the American Academy of Family Physicians, and the American Academy of Pediatrics. The vaccine was assumed to be administered alongside common compulsory vaccinations (tetanus, diphtheria), held in Italy three times within the first year of age. PCV-7 uptake was assumed to be the same as that reported by the Kaiser Permanent trial [9] (Table 1), with 82% compliance to three doses. Recently, in Italy a high uptake was reached for infant vaccinations, both compulsory and non compulsory ones [49,50]. However, uptake of novel noncompulsory vaccinations might be low for some years and increase with time, as it was the case for anti-Haemophilus conjugate vaccine. We, therefore, analysed different uptake hypotheses at sensitivity analysis.

Co-administration of tetravalent vaccine and PCV did not increase local and systemic reactions, except for febrile reactions on the day after the second dose [9,51]. Therefore, we attributed to PCV-7 a 1% rate of high fever after each administration (Table 1). At baseline, PCV-7 efficacy was modelled independently of vaccine coverage and of children age, according to the data reported by the Kaiser Permanente Study for overall IPD [9]. Since coverage for vaccine serotypes is countryspecific, we also run the analysis after adjustment for Italian-specific PCV-7 coverage [16]. Thirdly, we modelled an age-dependent strain-independent vaccine efficacy, as recently reported by a large post-licensure study in the US [52,53], and tested it at sensitivity analysis. PCV-7 efficacy against pneumonia was modelled according to intention-to-treat analysis of the Kaiser Permanente Study data, independently of aetiology of the event [40] and of pneumococcal serotype [41]. At sensitivity analysis we tested the hypothesis that efficacy against pneumonia was limited to events in the first 2 years of age [54]. Efficacy against otitis was similarly taken from intentionto-treat analysis of the Kaiser Permanente Study [9]. At sensitivity analysis, however, a distribution of values was analysed according to the reported confidence interval: the interval included efficacy rates provided by other studies [10], either with or without adjustment for country-specific proportion of pneumococcal otitis, which is 23%, according to the Italian Federation of Pediatricians [36]. Finally, we modelled that PCV-7 protection lasts up to 14 year of age, but efficacy was reduced by 3% each year after the fifth year of age, in order to represent declining protection rate and age-related shifts in predominant serotypes. This assumption was tested at sensitivity analysis. 2.6. Costs PCV-7 cost (year 2004) is D 88,40 [77], however, Italian law imposes a minimum 50% discount rate when drugs and vaccines are sold to hospitals and local health-care services [78]. We therefore adopted the acquisition cost that most of local health-care units applied for PCV-7 in the year 2004 [76]: the unit cost was approximated in order to avoid decimal figures. However, we performed an extensive sensitivity analysis on this input variable, in order to account for changing price politics in Italy and other countries. Administration costs were not considered at baseline analysis, since the vaccine was assumed to be co-administered alongside other vaccinations. However, this cost issue underwent sensitivity analysis [57]. Direct and indirect costs of pneumococcal complications (Table 2), namely meningitis, bacteraemia, pneumonia and acute otitis media, were estimated by an Expert Panel made of four community paediatricians, one hospital paediatrician and one infective disease research specialist [58]. The panel tracked the clinical pathways and specific resource

M. Marchetti, G.L. Colombo / Vaccine 23 (2005) 4565–4576

4569

Table 2 Baseline input clinical parameters Baseline value

Range

7.6/100000 2.1/100000 0.5/100000

2.3–8.0 0.4–3.0 0.1–1.0

Case fatality rate Age 0–1 Age 2–4 Age 5–10

14% 7% 1%

7–17% 2–10% 0–2%

Cost (direct)

D 20532 (D 7536)

D 16000–30000 (D 5000–12000)

12.7/100000 13.6/100000 3.3/100000

8–16 8–16 1–5

0.9% D 3816 (D 2916)

0–2% D 3000–5000 (D 2000–4000)

6.8/100000 5.2/100000 1.2/100000

3–8 3–8 0–2

0.9% D 3816 (D 2916)

0–2% D 3000–5000 (D 2000–4000)

0.89% 0.63% 0.15%

0–2% 0–2% 0–1%

D 2280.88 (D 1440.09)

D 1400–3000 (D 1000–2000)

23% 6%

20–60% 2–10%

1.24 D 236.68 (D 75.91)

1–1.8 D 150–300 (D 50–100)

PNC meningitis Yearly incidence Age <1 Age 1–4 Age 5–14

PNC bacteremia Yearly incidence Age <1 Age 1–4 Age 5–14 Case fatality rate Cost (direct) Other PNC IPD Yearly incidence Age <1 Age 1–4 Age 5–14 Case fatality rate (age 0–1) Cost (direct) Pneumonia Yearly incidence Age <1 Age 1–4 Age 5–14 Cost (direct) Otitis Yearly incidence Age 0–4 Age 5–14 Number of episodes per patient per year Cost (direct)

Source [1,25,28]

[1,35,31]

[58] [43]

[24] [58] [43]

[24] [58] [28]

[58] [36,31]

consumptions: the cost per episode was calculated with the support of a decision tree [58]. The visits were valued according to fees of Lombardy Region [59]. The direct cost for visits induced by a high fever in the days following vaccination was quantified according to official charges for specialist visits. We assumed that parents loose 3 h of paid work for the visit. Productivity loss was valued, according to the human capital approach, at an hourly wage of D 13 [60]. The model did not consider future productivity loss from infant premature death. 2.7. Analysis Baseline analysis was conducted both for the single patient and the whole birth cohort, and both in the societal and the

[36,39,31] [58]

NHS perspective. Undiscounted and discounted values were calculated: a 3% yearly discount rate was adopted, according to international guidelines [61]. One-way sensitivity analysis across wide ranges allowed to highlight the most relevant parameters. For incidence of events, efficacy rates and proportions we built beta distributions. Gamma distributions were built for input unit costs. A Poisson distribution represented the number of otitis episodes per patient. Distributions are detailed in the Appendix. A second-order Monte Carlo analysis was run onto 100,000 simulations and the acceptability curve of vaccination versus no vaccination was built. The 95% confidence interval (95% CI) of incremental cost-effectiveness ratio was calculated as the range between the 2.5% and the 97.5% percentile.

4570

M. Marchetti, G.L. Colombo / Vaccine 23 (2005) 4565–4576

Table 3 Baseline cost-effectiveness analysis (undiscounted) per patient and for the birth cohort of 538,138 infants (last column on the right)

Infections All IPD Meningitis Bacteraemia Pneumonia Otitis media (episodes/pt) Death due to IPD Life expectancy Direct medical costs IPD Pneumonia Otitis media Overall cost

Without vaccine

With vaccine

Difference

Absolutea

2.223 0.00165 0.000265 0.000978 0.0517 2.17 0.0000392 73.96530 (76.18426) D 221.1 (D 252.1) D 5.6 D 67.6 D 147.9 D 577.8 (D 660.2)

2.083 0.000237 0.000034 0.000144 0.0430 2.04 0.0000051 73.96776 (76.18679) D 315.1 (D 343.3) D 2.6 D 56.4 D 139.1 D 642.8 (D 718.8)

0.140 0.00143 0.000231 0.000834 0.087 0.13 0.0000341 0.00246 (0.00253) D 94.0 (D 91.1) D 3.0 D 11.2 D 8.8 D 64.9 (D 58.7)

75 769 124 449 46818 69,958 18 1323 (1361) MD 50.58 MD 1.61 MD 6.03 MD 4.73 MD 34.92

Incremental cost-effectiveness Direct medical cost per event averted Direct medical cost per IPD averted Direct medical cost per death averted Direct medical cost per life-year saved Overall cost per event averted Overall cost per IPD averted Overall cost per death averted Overall cost per life-year saved a

D /event averted D /event averted D /death averted D /LYS D /event averted D /event averted D /death averted D /LYS

Discounted

Undiscounted

671 1305555 2756891 38286 463 901388 1903225 26449

651 1266111 2673313 36046 419 815277 1721114 23205

M = millions.

3. Results 3.1. Baseline analysis The model calculated that the birth cohort considered would incur 888 episodes of IPD, 27,821 episodes of pneumonia and over 1.1 million episodes of acute otitis media. IPDs would cause 21 deaths. PCV-7 vaccination was calculated to prevent 769 IPDs and 18 deaths, therefore improving the cohort life expectancy by 1323 life years (Table 3). The number of infants needed to vaccinate in order to avoid one IPD episode was 699 and to avoid one death was 29,325. In the perspective of the NHS, PCV-7 would save D 23 per patient, due to averted infective episodes. In the perspective of the society, PCV-7 would save D 52 per patient. The net cost of universal vaccination, therefore, resulted to be higher in the NHS perspective and the incremental cost per life-year saved (LYS) was D 38,286, versus D 26,449 in the societal perspective (Table 3). Universal prophylaxis against S. pneumoniae would save D 12.3 and D 27.9 millions that would be sustained by the NHS and the society, respectively, for pneumococcal-related infections. Nevertheless, universal infant vaccination would impose a net burden of D 50.6 millions onto the NHS budget, and D 34.9 millions onto the society. 3.2. Sensitivity analysis One-way sensitivity analysis (Table 4) showed that IPD incidence and unit cost of vaccine were the pivotal vari-

ables of the analysis. Indeed, in some Italian regions a higher IPD rate has been recently reported [30,76]: were these data applied to the national model, incremental cost-effectiveness would decrease to D 10,479 and D 16,890 per LYS, in the society and NHS perspective, respectively (Table 4). Similarly, acquisition cost of vaccines may change according to several variables [77], therefore, policy makers need to consider this issue and recalculate the local cost-effectiveness of a universal PCV-7 program. Slight increments in unit cost of vaccine would still keep the incremental cost per LYS below the commonly accepted benchmark of D 50,000 per LYS: threshold unit costs were calculated to be D 60 per dose in the society perspective and D 49 per dose in the NHS one. Breakeven unit cost of PCV-7, i.e. the value at which induced savings equal induced costs, was D 8 per dose in the NHS perspective and D 18 per dose in the societal perspective. We also tested the possible application of a four-dose program, both in the ideal hypothesis of 100% uptake and in the realistic hypothesis that 3.3 doses per children are really administered [9]. Incremental cost-effectiveness ratio increased to a certain degree but did not sensibly overcame the commonly accepted benchmarks of D 40,000–50,000 per LYS (Table 4). By sensitivity analysis we could also verify the stability of the results at variations in input cost of pneumococcal disease (Table 4). In the hypothesis that the direct health-care costs for pneumonia, meningitis and otitis media were the lowest expected values, the cost-effectiveness of PCV-7 might not increase over D 41,139/LYS in the

M. Marchetti, G.L. Colombo / Vaccine 23 (2005) 4565–4576

4571

Table 4 One-way sensitivity analyses of discounted cost per life-year saved to changes in selected parameters Cost per LYS (societal perspective)

Cost per LYS (NHS perspective)

Baseline

26,449

38,286

Discount rate 0% 5%

23,205 28,377

36,046 39,673

Unit cost of vaccine D 20.00 D 60.00

3235 52,106

15,072 63,943

Number of dosesa 2.7 (US uptake for three doses)[9] 3.3 (Kaiser Permanente trial) [9] 4 (100% uptake of a four-dose program)

21,611 31,287 42,575

33,448 43,123 54,411

Administration cost D5 D 10

32,558 38,667

44,394 50,503

Yearly incidence of IPD 10.8/100.000 (years 0–2) [33] 58.9/100.000 (years 0–2) [31,76] 58.9/100.000 (years 0–4) [31,76]

46,640 13,813 10,479

65,764 21,014 16,890

Vaccine efficacy – IPD 57% 67% (coverage-adjusted) [9,16] Age-dependent (95% 1st year; 90% 2nd year; 68% 3rd–5th year; 0% >5th year) [52,53] 96%

43,370 31,325 35,986 34,360

61,052 44,524 51,117 35,474

Vaccine efficacy – otitis media 0% 10%

37,726 18,957

41,907 35,880

Vaccine efficacy – pneumonia 10% Age-dependent (22.7% <2nd year; 0% ≥2nd year) [54] 30%

29,537 28,740 21,258

40,235 39,732 35,008

Pneumonia incidence +50% +100%

22,836 19,222

36,004 33,723

Fatality rate – meningitis (age <2 years) 5% 17%

41,199 18,257

59,641 26,427

Otitis incidence (per patient; age 0–4) 0.15/year 0.40/year 0.60/year

29,322 20,341 13,156

39,208 36,324 34,017

Otitis incidence (per patient; age 5–14) 0%/year 2%/year

29,461 28,457

39,253 38,930

Protection period 5 years 10 years

32,694 28,343

43,115 39,767

Cost of pneumonia (total/direct) D 1400 (D 1000) D 1800 (D 1200)

29,240 27,973

39,680 39,046

Cost of meningitis (total/direct) D 16,000 (D 5000) D 18,000 (D 6000)

26,844 36,495

38,507 38,419

Cost of acute otitis media (total/direct) D 150 (D 50) D 200 (D 60)

31,960 30,040

39,985 39,601

a In

the hypothesis that efficacy does not change with the average number of doses administered.

4572

M. Marchetti, G.L. Colombo / Vaccine 23 (2005) 4565–4576

NHS perspective and over D 33,764/LYS in the societal perspective. In addition, we tested another relevant assumption in the model, i.e. that addition of PCV-7 to the current vaccination program would not increase the administration costs: this issue is quite relevant to the analysis, since the costeffectiveness of vaccination would greatly increase as all the administration costs are imputed to PCV-7 vaccination itself (Table 4). This issue, therefore, deserves further consideration and local evaluation by regional policy makers. We also examined the impact of different methods for modelling vaccine efficacy: coverage-adjustment and ageadjustment of vaccine efficacy against IPD increased the costeffectiveness ratio, but did not substantially change the results (Table 4). Also in the hypothesis that PCV-7 did not exert any efficacy after the age of 10, the vaccination program would cost D 28,343/LYS and D 39,767/LYS in the society and NHS perspective, respectively. 3.3. Monte Carlo analysis Monte Carlo analysis allowed us to calculate the confidence interval of the discounted cost-effectiveness ratios and to build the acceptability curves of universal pneumococcal vaccination in both the NHS and the societal perspective (Fig. 2). At second-order Monte Carlo simulation, the 95% CI of incremental cost-effectiveness ratio ranged from D 1975 to 62,075 per LYS in the societal perspective and from D 22,164 to 70,801 in the NHS perspective. The Monte Carlo analysis, therefore substantially confirmed that, at the national level, universal infant vaccination with PCV-7 is substantially costeffective. The acceptability curves (Fig. 2) showed that the largest portion of the simulated cases would attain a cost-effectiveness that is lower than commonly accepted benchmarks for health-care interventions, i.e. D 50,000 per LYS.

Fig. 2. Acceptability curve of PCV-7 universal infant vaccination versus no vaccination.

4. Discussion Preventive measures often induce low incremental utility to the single patient [62], and often require large investments at a high cost per unit of effectiveness achieved. However, society assign relatively high values to prevention of meningitis, pneumonia and complex otitis media [63], each adult individual being willing to trade 1 year of his personal life to avoid one episode of pneumonia in a child and 2 years to avert one episode of paediatric meningitis. Society is also willing to pay US$ 200–400 to reduce the individual risk of pneumonia by 0.5–0.9% and to pay US$ 500 to reduce the risk of meningitis by 0.015% [63]. The decision model we built projected that universal infant pneumococcal vaccination with PCV-7 was moderately costeffective in the Italian societal perspective, saving 1323 years of life per birth cohort at the cost of D 26,449 per LYS. Taking in consideration epidemiological data coming from Veneto [31] and Sardinia [75] regions, the PCV-7 vaccination results highly cost-effective determining a cost per LYS of D 10,479 (Table 4). The economic profile of PCV-7 for universal infant vaccination thus seems to be quite favourable in the Italian setting. Any universal vaccination has a great impact onto healthcare service budget, therefore, before implementation of large community programmes their economic impact need to be finely weighted against its potential health benefits. Italian preventive services would require D 62 millions in order to implement PCV-7 vaccination in each birth cohort, while the NHS would save over D 12 millions from averted infections. Universal extension and/or adoption of infant vaccinations compete for scarce health-care resources: the infant vaccinations actually implemented in Italy are either cost-saving, such as pertussis and hepatitis B vaccinations [64,65], or cost-effective, such as infant vaccination against Haemophilus influenzae type b, which would cost D 816,115 per averted death and D 11,637 per LYS [67]. On the contrary, universal infant vaccination against hepatitis A virus has not been implemented, since the cost per averted case of acute hepatitis would be very high [66]. Universal infant vaccination against S. pneumoniae induces a very low cost per averted case, i.e. D 463 versus D 19,576 with vaccination against H. influenzae type b, mainly due to acute otitis media episodes averted by PCV7. Moreover, in some regions PCV-7 has a similar costeffectiveness as anti-haemophilus vaccine, therefore, it seems that it should be implemented according to regional budgets. The cost-effectiveness of PCV-7 introduction in Italy seemed to be similar to the estimates for other countries, which have already adopted this preventive measure. In Table 5, we reported almost all the published costeffectiveness and cost-utility analyses for four European and three extra-European countries: Spain [55], Switzerland [22], The Netherlands [37], UK [68], Canada [56],

Table 5 Economic evaluations of infant vaccination with PCV-7 Country UK [68]

Australia [31]

Switzerland [22]

Canada [56]

The Netherlands [37]

US [69]

US [70]

Italy

360,000 4 doses Yes 61.3 <2 year

na 4 doses Yes na

250,000 4 doses No 70 <5years

80,000 4 doses Yes 18 <5 years

340,000 3 doses Yes 28 <10 yearsc

202,000 na No 16.5 <10 years

3,800,000 4 doses Yes 185.6 <2 years

1000 1–4 doses Yes –

538,000 3 doses No 22 (<5 years)

9.3%

na

11.5%; 7.1%

9%

6.6%

6.8%

5%

–

14%; 7%; 1%

1.2% Pn <2 year 120%/year <2 year 100% 10 years Yes Modelled Not modelled – 0%, 3%

na na na 10 years No Modelled Not modelled – 6% costs

0.03–0.65%/year 43–63%/year KPS 5 years No Modelled Not modelled DALY 0%, 5%

2.5%/year 49%/year na 10 years Yes Not modelled Not modelled – 3%

1.5%/year 22% na 10 years No Modelled Skin reactions QALY 4%

2.8%/year 1.18/year (<24mo) 100% Lifetime No Modelled Not modelled – 3%

33%/10years 5.06/10years 100% 10 years No Not modelled Not modelled – 3%

0.89%/year <2year 23%/year <5 year KPS Lifetime Yes Not modelled 1% high fever – 3%

Society perspective NHS perspective PCV-7 cost: PCV-7 breakeven cost/dose PCV-7 cost/otitis direct cost Vaccine efficacy on IPDd Coverage of PCV-7 for IPD Vaccine efficacy on pneumonia: Vaccine efficacy on otitis Duration of efficacy Cost-effectivenessf

Yes Yes na D 56.87 na 97.4% 64–83%e 11.4%

Yes Yes £39.25 0.50 97.4% 42–92% 6%

Yes No Aus$90 Aus$15.40 1 93.9% 83% 8.9% X-ray positive

0.6–0.66%/year 18–22.5%/year 70% 5 years No Modelled 5% high fever QALY 3% for long-term costs only Yes Yes CHF99 na 0.47 97%g 73% 11.4%g

Yes Yes Can$67.50 Can$50 0.25 89.1% na 11.4%

Yes No D 40 na 4 95% na 11.4%

Yes Yes $58 $46 ($18 NHS) 0.43 100% 80% 90% coverage (80%)a

Yes Yes na $52 0.52–0.58 – na 7%

Yes Yes D 39 D 16 (D 7 NHS) 0.51 89.1% 72% 17.7%

5.8% 10 years na

7% 10 years £31,512/LYS

5.8% 10 years 71,250 D /QALY

Monte Carlo

One-way

7%g 5 years 35,700–39,300 CHF/QALY One-way

5.8% 10 years 79,000 Can$/LYS

Sensitivity analysis

6.4% 5 years 230130 Aus$/LYS; 121100 Aus$/DALY One/two-way

Multi-ways

One-way

7% 5 years 80,000$/LYS (176,000 NHS) One-way

11% 10 years +D 88/infant; $15/adolescent One-way

6.4% 14 years 26,449 (38,286 NHS) D /LYS One-way, Monte Carlo

M. Marchetti, G.L. Colombo / Vaccine 23 (2005) 4565–4576

Spain [55] Birth cohort (size) Schedule Catch-upb Incidence of IPD (n/100.000/year) Case fatality rate of meningitis Incidence of pneumonia Incidence of otitis Vaccination uptake Time horizon Markov model Meningitis sequelae Vaccine adverse effects Quality of life Discount

Legend: na = not available; DALY = disability-adjusted life years; QALY = quality-adjusted life year; LYS = life-year saved. a Herd immunity was considered by no model. b Catch-up cohorts were usually modelled for children up to 6 years of age. c Includes meningitis and bacteriaemia. d Years 0–15 from vaccination, if complete uptake. e Depends on diagnosis (meningitis or not) and age. f Infant vaccination (catch up not considered). g The efficacy rates were adjusted for vaccine coverage.

4573

4574

M. Marchetti, G.L. Colombo / Vaccine 23 (2005) 4565–4576

Australia [31], US [69,70]. An economic evaluation was also conducted alongside the Kaiser Permanent trial: it showed that, after excluding the costs induced by vaccination per se, vaccination induced 1.2% savings in total medical costs, i.e. about US$ 78 per patient, mainly due to reduced visits for acute otitis media [71]. However, the trial was not powered to accurately assess differences in inpatient costs. This study has some limitations. First of all, our estimations are valid only for new birth cohorts and do not include the health and economic impact of catch-up vaccination. Second, we could not compare universal vaccination to targeted immunization according to underlying risk factors for pneumococcal disease [72]. Third, direct cost estimates for pneumococcal disease were not available [73]: our estimates were therefore based on resource utilization patterns reported by an Expert Panel. We are confident that the Expert Panel provided reliable figures, since the estimated cost of pneumonia was only D 5 higher than the reported hospital cost for 99 Italian children [74], and estimations for otitis media were very similar to the one reported in 191 episodes of rhinopharyngitis with/without otitis media [39]. Fourth, we did not model a series of potential benefits of vaccinations, namely herd immunity, the reduction of pneumonia severity and otitis recurrence and/or severity, possibly due to reduction of events sustained by penicillinresistant bacteria, and the decreasing incidence of other focal infections due to S. pneumoniae, such as sinusitis, arthritis, endocarditis. Fifth, input incidence rates for IPD, pneumonia and otitis media have high margins of uncertainty, especially regarding inter-regional differences, which could not be fully assessed: Monte Carlo analysis was necessary to include this uncertainty into the results. Sixth, we did not model long-term consequences of pneumococcal meningitis on either quality of life or costs, which induced an underestimation of the health and economic benefits of vaccination.

5. Conclusions Universal pneumococcal vaccination with PCV-7 in Italian infants is cost-effective, therefore, local policies need to be implemented, based on local epidemiology of pneumococcal disease and on local budgets.

Acknowledgements Conflict of interest: The authors declare that they have no other potential conflict of interest to report, nor would they financially benefit from the introduction of a mass immunisation program for infants with pneumococcal conjugate vaccine (Prevenar® ).

Appendix A Distribution details (TreeAge format) Variable

Type of distribution Parameter 1 Parameter 2 Beta

Efficacy on IPD on otitis on pneumonia Beta Incidence Pneumonia (year 0) Pneumonia (year 1–4) Pneumonia (year 5–14) Otitis (years 0–4) Otitis (years 5–14) Meningitis (years 0) Meningitis (years 1–4) Meningitis (years 5–14) Poisson Number of episodes Otitis

r

n

100 3378 33

112 52789 189

r

n

4450 12600 7500 3504 1839 38 42 25

500000 2000000 5000000 15237 15237 500000 2000000 5000000

Lambda 1.24

Gamma

Alpha

Beta

Costs

Input cost

1

References [1] Salmaso S, Mastrantonio P, Scuderi G, Congiu ME, Stroffolini T, Pompa MG, et al. Pattern of bacterial meningitis in Italy. Eur J Epidemiol 1997;13(3):317–21. [2] Principi N, Marchisio P. Epidemiology of Streptococcus pneumoniae in Italian children. Acta Paediatr Suppl 2000;89(435):40–3. [3] Barry AL. Antimicrobial resistance among clinical isolates of Streptococcus pneumonie in North America. Am J Med 1999;107(Suppl. 1A):28S–33S. [4] Moro ML, Pantosti A, Boccia D, gruppo EARSS-Italia. Antibiotic microbial resistance surveillance in invasive infections caused by Streptococcus pneumonie and Staphylococcus aureus: the European Antimicrobial Resistance Surveillance System (EARSS) project in Italy (April 1999–April 2000). Ann Ig 2002;14(5):361– 71. [5] Schito AM, Schito GC, Debbia E, Russo G, Linares J, Cercenado E, Bouza E. Antibacterial resistance in Streptococcus pneumonie and Haemaophilus influenzae from Italy and Spain: data from PROTEKT surveillance study. J Chemother 2003;15(3):226–34. [6] Marchese A, Debbia EA, Arvigo A, Pesce A, Schito GC. Susceptibility of Streptococcus pneumonie strains isolated in Italy to penicillin and ten others antibiotics. J Antimicrob Chemother 1995;36(5):833–7. [7] Pantosti A, D’Ambrosio F, Tarasi A, Recchia S, Orefici G, Mastrantonio P. Antibiotic susceptibility and serotype distribution of Streptococcus pneumoniae causing meningitis in Italy. Clin Infect Dis 2000;31(6):1373–9. [8] Straetemans M, Sanders EA, Veenhoven RH, Schilder AG, Damoiseaux RA, Zielhuis GA. Review of randomized controlled trials of pneumococcal vaccination for prevention of otitis media. Pediatr Infect Dis J 2003;22(6):515–24. [9] Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al. Efficacy, safety and immunogenicity of heptavalent

M. Marchetti, G.L. Colombo / Vaccine 23 (2005) 4565–4576

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19] [20] [21]

[22]

[23] [24] [25]

[26]

[27]

pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19(3):187–95. Eskola J, Kilipi T, Palmu A, Jokinen J, Haapakoski J, Herva E, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001;344(6):403–9. Dagan R, Melamed R, Muallem M, Piglansky L, Greenberg D, Abramson O, et al. Reduction of nasopharyngeal carriage of pneumococci during the second year of life by a heptavalent conjugate pneumococcal vaccine. J Infect Dis 1996;174(6):1271–8. Fireman B, Black SB, Shinefield HR, Lee J, Lewis E, Ray P. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J 2003;22(1):10–6. Ling Lin P, Michaels MG, Janosky J, Ortenzo M, Wald ER. Incidence of invasive pneumococcal disease in children 3 to 36 months of age at a tertiary care pediatric center 2 years after licensure of the pneumococcal conjugate vaccine. Pediatrics 2003;111(4):896– 9. Whitney CG, Farely MM, Hadler J, Harrison LH, Bennett NM, Lynfield R, et al. Decline in invasive pneumococcal disease after the introduction of protein–polysaccharide conjugate vaccine. N Engl J Med 2003;348(18):1737–46. Kaplan SL, Mason EO, Wald ER, Schutze GE, Bradley JS, Tan TQ, et al. Decrease of invasive pneumococcal infections in children among 8 children’s hospitals in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine. Pediatrics 2004;113(3):443–9. Pantosti A, Boccia D, D’Ambrosio F, Recchia S, Orefici G, Moro ML. National surveillance of bacterial meningitis; Earss-Italia study. Inferring the potential success of pneumococcal vaccination in Italy: serotypes and antibiotic resistance of Streptococcus pneumoniae isolates from invasive diseases. Microb Drug Resist 2003;9(Suppl. 1):61–8. Housdorff WP, Bryant J, Paradiso PR, Siber GR. Which pneumococcal serogroups cause the most invasive disease: implication for conjugate vaccine formulation and use, part I. Clin Infect Dis 2000;30(1):100–21. American Academy of Pediatrics. Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics 2000;106(2):362–66. Ministero dell’Economia e delle Finanze, Relazione Generale sulla Situazione Economica del Paese, 2003. ICONA study 2003. Vaccination uptake data. http://www.epicentro. iss.it/problemi/vaccinazioni/icona3 file/frame.htm. Brinsmead R, Hill S, Walker D. Are economic evaluations of vaccines useful to decision-makers? Case study of Haemaophilus influenzae type b vaccines. Pediatr Infect Dis 2004;23(1):32–7. Ess SM, Schaad UB, Gervaix A, Pinosh S, Szucs T. Costeffectievenss of a pneumococcal conjugate immunization program for infants in Switzerland. Vaccine 2003;21(23):3273–81. Sonnenberg FA, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making 1993;13(4):322–38. ISTAT, Annuario Statistico Italiano, 2002. http://demo.istat.it/. Pompa MG, Salmaso S, Caporali MG, Rizzuto E. Streptococcus pneumoniae meningitis in Italy—1994–98. Ann Ig 1999;11(4): 261–3. Principi N, Esposito S. Efficacy of the heptavalent pneumococcal vaccine against meningitis, pneumonia and acute otitis media in paediatric age. Theoretical coverage offered by the heptavalent conjugate vaccine in Italy. Ann Ig 2002;14(6 Suppl. 7):21–30. Moore MR, Gamble ML, Zell ER, Whitney CG. The active bacterial core surveillance/emerging infections program network, CDC, Atlanta GA. Deaths due to invasive Streptococcus pneumoniae, United States 1996–1998. In: Proceedings of the Poster Presented at 39th Annual Meeting of the Infectious Disease Society of America (IDSA). 2001.

4575

[28] Hospital Discharge Data (ICD-9 –based query). http://www. ministerosalute.it/programmazione/sdo/ric informazioni/sceltafine.jsp. [29] Marcos MA, Martinez E, Almela M, Mensa J, Jimenez de Anta MT. New rapid antigen test for diagnosis of pneumococcal meningitis. Lancet 2001;357(9267):1499–500. [30] Romano G, Poli A, Tardivo S, Chiamenti GP. Invasive pneumococcal diseases in age group 0–36 months: results from a perspective surveillance program in Nothern-eastern Italy. ISPPD 2004, Helsinki, Finlandia, 8–10 Maggio 2004 [Abstract number EPI 71]. [31] Butler JRG, McIntyre P, MacIntyre CR, Gilmour R, Howarth AL, Sander B. The cost-effectiveness of pneumococcal conjugate vaccination in Australia. Vaccine 2004;22(9–10):1138–49. [32] Laurichesse H, Romaszko JP, Nguyen LT, et al. Clinical characteristics and outcome of patients with invasive pneumococcal disease, Puy-de-Dome, France, 1994–1998. Eur J Clin Microbiol Infect Dis 2001;20(5):299–308. [33] von Kries R, Hermann M, Hachmeister A, Siedler A, Schmitt HJ, Al-Lahham A, et al. Prediction of the potential benefit of different pneumococcal conjugate vaccines on invasive pneumococcal disease in German children. Pediatr Infect Dis J 2002;21(11):1017– 23. [34] Swiss Pneumococcal Study GroupVenetz I, Schopfer K, Muhlemann K. Paediatric, invasive pneumococcal disease in Switzerlanddkjdot. Int J Epidemiol 1998;27(6):1101–4. [35] Totapally BR, Walsh WT. Pneumococcal bacteriemia in childhood. A 6-year experience in a community hospital. Chest 1998;113(5): 1207–14. [36] Indagine prospettica sull’epidemiologia delle otiti medie e carriage da S. pneumonite in et`a pediatrica: una esperienza italiana. XX Congresso Nazionale di Antibioticoterapia in et`a pediatrica, Milano, 23 November 2001. [37] Bos JM, Rumke H, Welte R, Postma MJ. Epidemiologic impact and cost-effectiveness of universal infant vaccination with a 7-valent conjugated pneumococcal vaccine in the Netherlands. Clin Ther 2003;25(10):2614–30. [38] Pukander J, Luotonen J, Sibila M, Timonen M, Karma P. Incidence of acute otitis media. Acta Otolaryngol 1982;93(5-6):447–53. [39] Van Cauwenberge P, Berdeaux G, Morineau A, Smadjia C, Allaire J-M, Rhinitis Survey Study Group. Use of diagnostic clusters to assess the economic consequences of rhinopharyngitis in children in Italy and France during winter. Clin Ther 1999;21(2): 404–21. [40] Esposito S, Madore DV, Bosis S, et al. Characteristics of Streptococcus pneumoniae and atypical bacteria infections in children 2–5 years of age with community-acquired pneumonia. Clin Infect Dis 2002;35:1345. [41] Esposito S, Madore DV, Gironi S, Bosis S, Tosi S, Bianchi C, et al. Theoretic coverage of heptavalent pneumococcal conjugate vaccine in the prevention of community-acquired pneumonia in children in Italy. Vaccine 2003;21(21–22):2704–7. [42] http://www.ricercaesanita.it/medicinaesanita/bohegenn.PPT. [43] Hospital Discharge Data (DRG-based query) http://www. ministerosalute.it/programmazione/sdo/ric informazioni/sceltadrg.jsp. [44] Monge V, Gonzalez A. Hospital admissions for pneumonia in Spain. Infection 2001;29(1):3–6. [45] Shah SS, Alpern ER, Zwerling L, McGowan KL, Bell LM. Risk of bacteremia in young children with pneumonia treated as outpatients. Arch Pediatr Adolesc Med 2003;157(4):389–92. [46] Mufson MA, Stanek RJ. Bacteremic pneumococcal pneumonia in one American City: a 20-year longitudinal study. Am J Med 1999;107(1A):34S–43S. [47] Toikka P, Virkki R, Mertsola J, Ashorn P, Eskola J, Ruuskanen O. Bacteremic pneumococcal pneumonia in children. Clin Infect Dis 1999;29(3):568–72. [48] Pineda Solas V, Perez Benito A, Domingo Puiggros M, Larramona Carrera H, Segura Porta F, Fontanals Aymerich D. Bacteremic pneumococcal pneumonia. An Esp Pediatr 2002;57(5):408–13.

4576

M. Marchetti, G.L. Colombo / Vaccine 23 (2005) 4565–4576

[49] ICONA Study GroupSalmaso S, Rota MC, Ciofi Degli Atti ML, Tozzi AE, Kreidl P. Infant immunization coverage in Italy: estimates by simultaneous EPI cluster surveys of regions. Bull World Health Organ 1999;77(10):843–51. [50] http://www.epicentro.iss.it/problemi/vaccinazioni/sintesi-icona.htm. [51] Obaro SK, Enwere GC, Deloria M, Jaffar S, Goldblatt D, Brainsby K, et al. Safety and immunogenicicty of pneumococcal conjugate vaccine in combination with diphteria, tetanus toxoid, pertussis and Haemophilus influenzae type b conjugate vaccine. Pediatr Infect Dis 2002;21(10):940–6. [52] Black SB, Shinefield HR, Hansen J, Elvin L, Laufer D, Malinoski F. Postlicensure evaluation of the effectiveness of seven valent pneuococcal conjugate vaccine. Pediatr Infect Dis J 2001;20(12):1105–7. [53] Black S, Shinefield H, Baxter R, Austrian R, Bracken L, Hansen J, et al. Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente. Pediatr Infect Dis J 2004;23(6):485– 9. [54] Black SB, Shinefield HR, Ling S, Hansen J, Fireman B, Spring D, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J 2002;21(9):810–5. [55] Asensi F, De Jose M, Lorente M, Moraga F, Ciuryla V, Arikian S, et al. Pharmacoeconomic evaluation of seven-valent pneumococcal conjugate vaccine in Spain. Value Health 2004;7(1):36–51. [56] Lebel MH, Kellner JD, Ford-Jones EL, Hvidsten K, Wang EC, Ciuryla V, et al. A pharmacoeconomic evaluation of 7-valent pneumococcal conjugate vaccine in Canada. Clin Infect Dis 2003;36(3):259–68. [57] Bigini R, Bonaccorsi G, Isola A. Due casi di tetano nel territorio della Valdinievole: come e perch´e possono ancora verificarsi episodi di una malattia di classe prima evitabile mediante intervento vaccinale. Atti della Sezione Toscana della Siti – Seduta Scientifica 15/11/1996, 1997. pp. 55–62. [58] Colombo GL. Cost-of-Illness delle malattie pneumococciche nel bambino in Italia. Ann Ig 2002;14(5):373–88. [59] Regione Lombardia, Tariffario Regionale delle prestazioni di assistenza specialistica ambulatoriale, Gennaio 2004. [60] ISTAT, Annuario Statistico Italiano, 2002. http://demo.istat.it/. [61] Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the Panel on Cost-effectiveness in health and medicine. JAMA 1996;276(15):1253–8. [62] Wright JC, Weinstein MC. Gains in life expectancy from medical interventions—standardizing data on outcomes. N Engl J Med 1998;339(6):380–6. [63] Prosser LA, Ray GT, O’Brien M, Kleinman K, Santoli J, Lieu TA. Preferences and willingness to pay for health states prevented by pneumococcal conjugate vaccine. Pediatrics 2004;113(2):283–90.

[64] Beutlers P, Bonanni P, Tormans G, Canale F, Cuneo Crovari P. An economic evaluation of universal pertussis vaccination in Italy. Vaccine 1999;17(19):2400–9. [65] Da Villa G, Sepe A. Immunization programme against hepatitis B virus infection in Italy: cost-effectiveness. Vaccine 1999;17(1314):1734–8. [66] Demicheli V, Carniglia E, Fucci S. The use of hepatitis A vaccination in Italy: an economic evaluation. Vaccine 2003;21(19–20):2250–7. [67] De Campora E, Pizzuti R. Use of the economic evaluation in the comparison of different vaccination programs against Haemophilus influenzae type b disease. Ann Ig 1995;7(5):329–38. [68] McIntosh ED, Conway P, Willingham J, Lloyd A. The cost-burden of pediatric pneumococcal disease in the UK and the potential costeffectiveness of prevention using 7-valent pneumococcal conjugate vaccine. Vaccine 2003;21(19–20):2564–72. [69] Lieu TA, Ray GT, Black SB, Butler JC, Klein SO, Breiman RF, et al. Projected cost-effectiveness of pneumococcal conjugate vaccination of health infants and young children. JAMA 2000;283(11):1460–8. [70] Weycker D, Richardson E, Oster G. Childhood vaccination against pneumococcal otitis media and pneumonia: an analysis of benefits and costs. Am J Manage Care 2000;6(Suppl. 10):S526–35. [71] Ray GT, Butler JC, Black SB, Shinefield HR, Fireman BH, Lieu TA. Observed costs and health care use of children in a randomized controlled trial of pneumococcal conjugate vaccine. Pediatr Infect Dis J 2002;21(5):361–5. [72] Levine OS, Farley M, Harrison LH, Lefkowitz L, McGeer A, Schwartz B. Risk factors for invasive pneumococcal disease in children: a population-based case-control study in North America. Pediatrics 1999;103(3):28. [73] Elies W, Pletan Y. An international medico-economic survey of 2007 children with recurrent nasopharyngitis and acute otitis media. Drugs 1997;54(Suppl. 1):5–12. [74] Di Ciommo V, Russo P, Attanasio E, DI Liso G, Graziani C, Caprino L. Clinical and economic outcomes of pneumonia in children: a longitudinal observational study in an Italian paediatric hospital. J Eval Clin Pract 2002;8(3):341–8. [75] Castiglia P, Gallisai D, Sotgiu G, Maida A, Group for Sourveillance on Pneumococcal Infections. Epidemiology of invasive pneumococcal infections in Sardinian children. In: Proceedings of the 4th International Symposium on Pneumococci and Pneumococcal Diseases, Helsinki, Finland, 9–13 May 2004. Poster presentation. Abstract number EPI 19. [76] Regione Piemonte. Gara 1/2003. G326A. [77] Italian Ministry of Health. Cost of drugs and vaccines. http://www.guidausofarmaci.it/pag14020.htm [accessed on April 2005]. [78] Art. 9, Law n. 386/74 of the Italian Health Ministry, 17th August 1974.