Emerging Infectious Diseases [Volume 5 No.3 / May - June 1999] Perspectives The Cost Effectiveness of Vaccinating against Lyme Disease Martin I. Meltzer, David T. Dennis, and Kathleen A. Orloski Centers for Disease Control and Prevention, Atlanta, Georgia, USA --------------------------------------------------------------------------- To determine the cost effectiveness of vaccinating against Lyme disease, we used a decision tree to examine the impact on society of six key components. The main measure of outcome was the cost per case averted. Assuming a 0.80 probability of diagnosing and treating early Lyme disease, a 0.005 probability of contracting Lyme disease, and a vaccination cost of $50 per year, the mean cost of vaccination per case averted was $4,466. When we increased the probability of contracting Lyme disease to 0.03 and the cost of vaccination to $100 per year, the mean net savings per case averted was $3,377. Since few communities have average annual incidences of Lyme disease >0.005, economic benefits will be greatest when vaccination is used on the basis of individual risk, specifically, in persons whose probability of contracting Lyme disease is >/=0.01. Lyme disease, caused by infection with Borrelia burgdorferi, is the most common tick-borne disease in the United States and Europe (1-3). In the United States, the disease has spread slowly, and the number of cases in disease-endemic areas has increased (4-6). Most Lyme disease patients become infected with B. burgdorferi near their homes, while engaged in property maintenance, recreation, and relaxation (7). Occupational and recreational activities away from home may also pose a risk (8). Lyme disease prevention based primarily on avoidance of tick bites, use of repellants, early detection and removal of attached ticks, and tick control has not substantially reduced disease incidence (4-6). Therefore, preventive vaccines have been of considerable interest. Results of randomized and blinded phase-III field trials with recombinant B. burgdorferi outer surface protein A (rOspA) vaccines indicate that they are safe and efficacious (9,10). On December 21, 1998, the U.S. Food and Drug Administration licensed one of the vaccines (LYMErix, SmithKline Beecham Biologicals, Reixensart, Belgium) for use in the United States (11). We present the results of an analytic model that evaluates the cost effectiveness of using a vaccine to protect against Lyme disease in the United States. The Model Using a computer-based spreadsheet (Excel 5.0 for Windows, Microsoft), we constructed a decision tree (12) to evaluate the cost per case averted (cost effectiveness) to society of vaccinating against Lyme disease (Figure 1). Many data needed to determine the cost effectiveness of vaccinating against Lyme disease are unvalidated, unavailable, or available only from very small databases. Thus, rather than calculate a single estimate of cost per case averted, we examined the effect of combinations of six inputs: cost of vaccination; annual probability of contracting Lyme disease; costs of successfully treating either early symptoms of Lyme disease or one of three sequelae (cardiovascular, neurologic, arthritic); probability of diagnosing and treating early symptoms; probability of sequelae due to early infection; probability of sequelae due to late, disseminated infection. Mathematically, we examined the effect [Fig] of altering the values of the inputs by using specialized computer software Fig 1. Decision tree to model (@Risk, Palisade Corp., Newfield, NY) the cost effectiveness of (13) that employs Monte Carlo methods vaccinating a person against (14-16). To use these methods, the Lyme disease. researcher defines probability distributions for selected inputs by using available data and enters them into the computer program. For each iteration of the program, an algorithm selects input values from the probability distributions, calculates the net result (here, the cost per case averted), and stores that result. After all iterations (typically 1,000 to 5,000) are completed, the program produces a probability-based distribution of the net result, which can then be used to report statistics such as mean, median, and 5th and 95th percentiles. Cost Effectiveness Formula The formula used to calculate the cost per case of Lyme disease averted was as follows: Cost per case averted = ($ of vacc+$of LD with vacc-$ of LD without vacc)/ (Prob LD without vacc-Prob LD with vacc) where $ = cost; vacc. = vaccination; LD = Lyme disease; and prob. = probability. The numerator is the cost of vaccination less any savings resulting from the reduced probability of contracting the disease (decreased incidence) due to vaccination. If the vaccine is not 100% effective in preventing Lyme disease (i.e., if the term Prob. LD with vacc. >0), treatment costs may still be incurred after vaccination. The cost of a case of Lyme disease is the weighted average cost of all health outcomes (Figure 1), where the weights are the probabilities of those outcomes 12). The denominator reflects the change in the probability of Lyme disease due to vaccination. Vaccine Timeline Although experiments have shown that a Lyme disease vaccine using rOspA is safe and immunogenic in both animals and humans (17-23), no data have been published concerning the decrease in antibody levels over more than 20 months (9). Phase-III vaccine field trials used a 0-, 1-, and 12-month immunization schedule, and antibody levels dropped almost 10-fold between the month after the second dose and just before the third dose at month 12 (9). The third dose at month 12 boosted antibodies to levels higher than measured at month 2, but these declined by half by month 20 (9). We assumed, therefore, that an annual booster dose would be required and that the cost-effectiveness model would be repeated annually. When calculating annual benefits, however, we included the discounted savings of preventing Lyme disease that may generate multiyear sequelae. Lyme Disease Symptoms and Sequelae The most common symptoms of infection with B. burgdorferi can be categorized as early localized disease (stage I); early disseminated disease (stage II); and later stage sequelae of disseminated infection-(stage III) (24). Stages I and II correspond to the branches labeled "Recognize early LD? Yes" in Figure 1, and stage III corresponds to the branches labeled "Recognize early LD? No." Most early symptoms of Lyme disease respond promptly and completely to short courses of oral antibiotics (25-27). Later-stage sequelae, however, may require costly, more prolonged treatment, sometimes repeated courses of treatment using intravenous cephalosporins, and may not be completely eliminated (28). If a person, vaccinated or unvaccinated, contracts Lyme disease, the model allows for one of four possible categories of outcomes (Figure 1) (29-31): cardiovascular sequelae (e.g., high-grade atrioventricular blocks); neurologic sequelae (e.g., isolated cranial nerve palsy, meningitis); arthritic or rheumatologic/musculoskeletal sequelae (e.g., episodic oligoarticular arthritis, arthralgia); and case resolved (after a course of an oral antibiotic such as doxycycline) with no further complications. The disseminated stages of Lyme disease may be manifested weeks to months after infection (24). However, few data concerning the duration of such sequelae are available. One study, for example, involving 38 patients showed that their long-term clinical sequelae lasted a mean of 6.2 years from onset of disease (32). The use of health-care resources, however, by those patients during that time was not reported. We assumed that cardiovascular sequelae would be treated and resolved in an average of 1 year and that late neurologic and arthritic sequelae would both take an average of 11 years to diagnose and satisfactorily treat to full resolution (initial year of diagnosis and treatment plus 10 years of additional treatment). These assignments of average time are arbitrary and longer than any published average, which maximizes estimated economic benefits of using a vaccine. Probabilities We selected three probabilities (0.005, 0.01, and 0.03) of contracting Lyme disease (Table 1) on the basis of data concerning disease incidence in Lyme disease-endemic areas ((33-36); the probability of 0.03 is among the highest reported. (Before the risk for Lyme disease was widely recognized, a one-time annual incidence of 10% was reported in a community of 190 people living next to an open nature preserve [37].) Vaccine efficacy in preventing Lyme disease was 50% (95% confidence intervals [CI]: 14% to 71%) after the first two doses and 78% (95% CI: 59% to 88%) after three doses (9,11). Table 1. Probabilities and their statistical distributions --------------------------------------------------------------------------- Item Values Type of distribution(sup a) --------------------------------------------------------------------------- Probability of contracting LD(sup b) 0.005, 0.01, 0.03 Fixed intervals (sup c) Effectiveness of vaccine 0.85 Fixed Probability of early Fixed intervals (sup c,d) detection of LD 0.6 - 0.9 Probability of sequelae (sup e) if detect LD early Cardiac 0 - 0.01 Uniform (sup f) Neurologic 0 - 0.02 Uniform (sup f) Arthritic 0.02-0.05-0.07 Triangular (sup g) Case resolved Residual (sup h) N/A Probability of sequelae if do not detect LD early Cardiac 0.02-0.03-0.06 Triangular Neurologic 0.02-0.15-0.17 Triangular Arthritic 0.5-0.6-0.62 Triangular Case resolved Residual (sup h) N/A --------------------------------------------------------------------------- (sup a) Statistical distribution used in Monte Carlo simulations (14-16). (sup b) LD = Lyme disease. (sup c) Iterations are run by using different combinations of the probabilities of infection and cost of treatment (Table 2). (sup d) The interval between the minimum and the maximum is divided into 0.1 increments. (sup e) See text for description of sequelae. (sup f) Uniform distribution implies that there is an equal chance that any number between, and including, the minimum and maximum will be used for a given iteration. (sup g) Triangular distribution is defined by points of minimum, most likely, and maximum. (sup h)The probability of an LD case being successfully resolved (i.e., no further sequelae) is 1 - (sum of the probabilities of cardiac + neurologic + arthritic symptoms). We assumed Lyme disease vaccine to be 85% effective, which is near the upper end of the 95% confidence limits and thus maximizes estimated economic benefits. We selected 0.6 to 0.9 as the range of probability of early diagnosis and treatment on the basis of a study on the economic cost of Lyme disease, which included data from an expert panel (38). For the Monte Carlo simulations (14-16), we constructed the distributions describing the probabilities of having one of the three sequelae (due to either early or late disseminated disease) using data from the previously mentioned expert panel (Table 1) (38). The distributions describing cardiac and neurologic complications associated with early Lyme disease are uniform, defined by using minimum and maximum values (39) and reflecting the uncertainty regarding a most likely value (38). All other distributions are triangular (39), with minimum, most likely, and maximum values (Table 1). Vaccination Costs Although a Lyme disease vaccine has been licensed (11), data are not available on the actual cost of vaccination, which includes costs of the vaccine, its administration, time spent in receiving the vaccine, travel, and treatment of adverse side-effects of vaccination. To allow for variation caused by variables such as location of provider, type of provider, and type of third-party payer, we estimated cost effectiveness by using three costs: $50 per person per year, $100 per person per year, and $200 per person per year. Few data are available on the costs of treating a case of Lyme disease; only one study (29) has documented the charges in 1989 dollars associated with some sequelae. To adjust charges reported in that study to 1996 prices, we multiplied the charges by a factor of 1.528 (medical care component of the consumer price index) (40). These 1996 prices, however, reflected health-care charges paid by health insurance companies and not necessarily actual economic costs (41,42). Thus, to reflect economic costs, the adjusted prices were multiplied by cost-to-charge factor (the weighted average of the urban and rural hospital cost-to-charge ratios used by the U.S. Federal Health Care Finance Administration [43]) of 0.53. Data describing indirect costs, particularly lost productivity, associated with sequelae were unavailable. We therefore assumed that Lyme disease–related cardiac sequelae would cause 14 days of lost productivity, and neurologic and arthritic sequelae would each cause 21 days of lost productivity per year. Each day of lost productivity was valued at $100 (the average income of a workday [1990 dollars inflated to 1996 values] weighted by the age and sex composition of the U.S. workforce) (44). Because we assumed that late-stage neurologic and arthritic complications may take up to 11 years to completely resolve, the 1-year cost estimates for treating these sequelae were replicated over 11 years and then discounted at 3% to the base year (Table 2). Table 2: Costs of treating one case of Lyme We also disease and the sequelae due to early and late altered disseminated disease the estimate ----------------------------------------------------------------- of Magid Cost/ Length Total et al. year of treat- costs(sup a)(29) of Item ($) ment ($) charges for ----------------------------------------------------------------- resolving Case resolved: no sequelae a case Antibiotics 14 of Lyme disease Office visits (2) 50 without Laboratory tests 35 complications 5 hrs lost work time 62 by doubling Total 161 2-3 wks 161 the Sequelae (sup b)due to early and number late disseminated disease of office Cardiac-direct(sup c) 5,445 visits Cardiac-indirect (sup d) 1,400 to two ($25 Cardiac-total 6,845 /= for greater than or equal to.