Elsevier

Vaccine

Volume 19, Issues 11–12, 8 December 2001, Pages 1416-1424
Vaccine

Pre-exposure rabies vaccination: strategies and cost-minimization study

https://doi.org/10.1016/S0264-410X(00)00368-6Get rights and content

Abstract

An alternative strategy for pre-exposure rabies vaccination to the institutional recommendations of the World Health Organization and the Centers for Disease Control and Prevention is proposed based on recent long-term follow-up of post-vaccinal seroconversion rates. The alternative strategy uses the same primary series (i.e. vaccination in the deltoid area on D0, D7, and D28), but is completed by a scheduled booster vaccination at D365. The frequency of recommended subsequent booster injections depends on the serological test results obtained by a RFFIT on D379 and 3 years later. The objective of this study was to compare the efficiency of the two pre-exposure strategies. A cost-minimization analysis was carried out to compare the two rabies pre-exposure vaccination and serological test strategies based on the data from two published studies on the long-term evolution of the immunity achieved using the different recommendations. For a theoretically equivalent immunogenicity, the cost of the alternative strategy ranged from 1.7 to 5.2 times lower than that of the institutional recommendations. A sensitivity analysis confirmed the robustness of the results. The alternative strategy should be validated externally under field conditions. This approach would compare its real efficiency to the institutional recommendations.

Introduction

The recommendations of the World Health Organization (WHO) [1] and Advisory Committee of Immunization Practices of the Centers for Disease Control and Prevention (CDC) [2] for pre-exposure rabies vaccination include the administration of three injections of a cell culture vaccine given intramuscularly in the deltoid area on days 0, 7, and 21 or 28. Titration of neutralizing antibodies by a standardized Rapid Fluorescent Focus Inhibition Test (RFFIT) is recommended to assess the seroconversion of the subjects at high risk for exposure to the virus, with a frequency adapted to that risk. A subject is considered to have seroconverted when the antibody level is ≥0.50 IU/ml [1] or with complete virus neutralization at a 1:5 serum dilution [2]. For persons at continuous risk (e.g. workers in production or research laboratories in the field of rabies), antibody levels should be assessed every 6 months. In case of frequent risk (e.g. rabies diagnostic laboratory workers, spelunkers, veterinarians and staff, and animal-control and wildlife workers in rabies-enzootic areas), the WHO and the CDC, respectively recommend antibody level assessment every 1 and 2 years. In all cases, boosters should be given as soon as the subject is found to be seroreverted (i.e. when the titer falls below 0.50 IU/ml). If the risk is considered to be infrequent (e.g. veterinarians and animal-control and wildlife workers in areas with low rabies rates, veterinary students, travelers visiting areas where rabies is enzootic and immediate access to appropriate medical care including biologics is limited), the WHO does not issue any recommendation, while the CDC indicates that there is no need for serological tests or routine booster injections.

We previously conducted a prospective study on the 10 year follow-up of seroconversion rates (SCR) and antibody levels obtained after pre-exposure rabies vaccination [3], [4]. In particular, our last study demonstrated the long-term immunogenicity of the 3-injection regimen (D0, D7, and D28) completed by a scheduled booster injection at 1 year (D365) [4]. The cell-culture vaccines used during this study were the human diploid cell rabies vaccine (HDCV) [5], [6], used in the USA, and the vaccine prepared on Vero cells (PVRV) [7], [8], used in France and in 41 other countries in which 15 million doses have been distributed. Vaccines were administered intramuscularly in the deltoid. An alternative strategy to the institutional recommendations of the WHO and the CDC as regards antibody serological tests and booster injections was suggested based on the results of this study.

The proposed alternative strategy is based on antibody level assessment at times that are particularly predictive of the evolution of the SCR and antibody titers over the 10 year follow-up period as determined by a multivariate analysis of our prospective study [3], [4], [9]. On D379 (i.e. 14 days after booster at 1 year), a titer ≥30 IU/ml had a positive, predictive seroconversion value of 100% at 10 years while a titer <30 IU/ml had a negative, predictive seroconversion value of 18%. In other words, a subject with a titer of at least 30 IU/ml on D379 would definitely still be seroconverted after 10 years. Conversely the likelihood of seroreversion in subjects with a titer of <30 IU/ml on D379 was 18% at 10 years. In addition, if subjects seroreverted they did so between the second and third year after D379. Thus, at D379+3 years, 100% of subjects who had a titer ≥0.5 IU/ml were still seroconverted at 10 years. In contrast, subjects with titers <0.5 IU/ml at this time were considered to be low responders [10], for whom subsequent serial scheduled booster vaccinations could be justified. We thus identified these two preferred times (i.e. D379 and D379+3 years) as being particularly indicative of an individual's serological evolution, and these timepoints were chosen for the scheduled measurements of antibodies in the alternative strategy [9].

The neutralizing antibody titer, as an efficacy criterion for pre-exposure anti-rabies vaccination is a point worth discussing. Since rabies is a 100% fatal disease, any vaccination strategy has to guarantee total protection from exposure, and the efficacy of the program can not be sacrificed in any optic of saving costs. However, the paradox is that, due to the nature of the disease, ethically it is not possible to obtain any clinical evaluation of the efficacy of a rabies vaccination program. The only possible criterion available is this neutralizing antibody titer. This is the consensual criterion of immunogenicity in the clinical evaluation of rabies vaccines [1], [2], [11]. It is this criterion which has been used in the cost minimization analysis and the immunogenicity of a strategy was expressed by the SCR observed in the cohort of subjects submitted to this strategy.

Although cost-minimization studies have been used to compare the economic values of various drug regimens, they have been infrequently employed to compare vaccination strategies. The objective of this present study was to use this pharmacoeconomic approach to compare the efficiency of the two pre-exposure strategies, which differ in their pre-exposure vaccination protocol and assessment of persistence of measurable immune response through antibody serological measurements.

Section snippets

Choices and assumptions

The efficiency of the two strategies was assessed using a cost-minimization decisional analysis [11], assuming that immunogenicity was equivalent in both cases and considering the direct cost of vaccination, boosters, and antibody serological tests over a 10 year period.

The results of our prospective study [4] suggested that at 10 years, the immunogenicity of pre-exposure vaccination obtained with the alternative strategy (SCR=0.968) was higher than that achieved with the institutional

Results

The average cost of the alternative strategy was US$ 155 per subject for 10 years (Fig. 1 and Fig. 2, branches 2, 4, and 5). Considering persons at continuous risk of exposure (Fig. 1), the cost of the alternative strategy was 5.1 times lower than that of the institutional recommendations (WHO and CDC) (US$ 798; branches 6 and 7). Likewise, for a frequent risk of exposure (Fig. 2) the cost was less than that of the institutional recommendations, although the difference was not as great: US$ 431

Discussion

Pre-exposure rabies vaccination has two perfectly complementary objectives. First, it must protect against unrecognized exposure, especially in the case of subjects whose occupations continually or frequently expose them to the virus. Second, it must anticipate exposure when isolated situations in the field do not permit post-exposure treatment to be administered under reliable conditions. In this latter respect, pre-exposure vaccination provides psychological security, enables reliable medical

Acknowledgements

We thank S.A. Plotkin, F. Medina and S. Wood for their thoughtful comments and contributions. Financial support: Pasteur Mérieux Connaught.

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