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

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.

[Rabies in France: an update]. / La rage en France: actualité.

INTRODUCTION: In 1996, rabies was responsible for more than 35,000 deaths worldwide. Three cases of human rabies that had been contracted abroad were diagnosed in France during the same year. Cases notified in 1997 followed exposure outside the country. Fox, bat, and dog rabies are reviewed on the basis of the latest epidemiological data obtained in France. CURRENT KNOWLEDGE AND KEY POINTS: Two cases of fox rabies diagnosed in 1998 occurred at the border between France and Germany, thus preventing five French departments bordering Germany from being officially declared rabies-free in 1999. The campaigns for oral immunization of foxes that are led since 1986 are responsible for the decrease in rabies incidence. Though not well known, bat rabies is a reality in France, involving either European virus strains (five cases all over the country) or African virus strains that are carried along by imported tropical bats. Dogs rabies is also today an imported disease. FUTURE PROSPECTS AND PROJECTS: The decrease in risk for rabies has resulted from the conjunction of multiple efforts: extensive programs aimed at oral vaccination of foxes in France and its neighboring countries, efficient epidemiological survey, sanitary controls at borders, ban on importing tropical bats. Furthermore, recommendations for preventive pre-exposure immunization have recently been changed, leading to modifications of the French licensing form.

[Prevalence of infection by hepatitis viruses in a rural area. Analysis according to risk factors and alcohol consumption]. / Prévalence des infections par les virus hépatotropes en milieu rural. Analyse en fonction des facteurs de risque viraux et de la consommation d'alcool.

OBJECTIVES: To evaluate the prevalence of serum markers of hepatitis A, B and C viruses in a rural area according to risk factors and alcohol consumption. METHODS: Transversal study of unselected subjects living and working in a rural area. Each subject included was asked to fill out an anonymous self-administered questionnaire dealing with his own risk factors, sexual behaviour and alcohol consumption. A blood sample was collected for detection of HBsAg, anti-HBc, anti-HBs, anti-HAV and anti-HCV antibodies. RESULTS: Three hundred three subjects with a mean age of 48 years were included. Main risk factors for viral infection were: blood transfusion (9.4%), intravenous drug addiction (0.73%), acupuncture (17.5%), tattoos (5. 8%), past hospitalizations (71.5%), homosexuality (1.1%), conjugal unfaithfulness (11%), sexual partners >5 (21.3%). Most subjects with at risk sexual behaviour had sexual relations without protection. Anti-HAV prevalence was 87.2% (95% confidence interval 83.4-91.0%). None of the subjects was HBsAg positive and 6.0% (confidence interval 4.7-8.7%) had anti-HBV antibodies. HBV prevalence was correlated to homosexuality only. Two subjects (0.67%, confidence interval 0-1.6%) without any identified risk factor had anti-HCV antibodies. There was no correlation between serum viral marker positivity and an excess alcohol consumption (>80 g of ethanol/d) which was present in 46 subjects. However HBV prevalence was 28.6% in the seven subjects who had been treated for alcoholism; these 7 subjects had a highly at risk sexual behaviour. CONCLUSION: In a rural area, infection by HAV is very frequent. The prevalence of HBV and HCV did not greatly differ from that observed in the general and urban population. The frequent failure to use protection in subjects with at risk sexual behaviour reinforces the need of prevention programs in rural areas.

Predictive factors for the neutralizing antibody response following pre-exposure rabies immunization: validation of a new booster dose strategy.

A prospective cohort of 312 subjects who received pre-exposure rabies immunization and who were monitored serologically with a 10-year follow-up was assessed using multivariate analysis. The aim was to propose a new booster dose strategy by identifying predictive factors for the durability of the neutralizing antibody response. Evaluation bore on several factors relating to: (1) demographic characteristics: age, gender; (2) vaccines: type of vaccine (HDCV or PVRV), injection regimen (D0-D28-D365 or D0-D7-D28-D365) and vaccine lots' antigenic potency; and (3) resulting antibody titers. Logistic regression analysis enabled the authors to establish a predictive model for immunized subjects' serological status at ten years' follow-up expressed as a P probability for seroreversion (antibody titer <0.5 IU/ml). Highly significant factors were the immunization regimen, the type of vaccine used and the antibody titer at D379. A P value <0.4 identified subjects as "good" responders who were sure to be have satisfactory antibody titers at 10 years and who required a single booster dose every 10 years. A P value >/=0.4 identified subjects as "poor" responders in whom a specific follow-up and booster dose strategy is proposed. This new immunization strategy could at least be applied to subjects with a frequent risk of exposure, as defined by institutional recommendations. This new immunization strategy should nevertheless undergo an external validation and a cost-effectiveness evaluation.

Expression of interferons-alpha and -gamma in testicular interstitial tissue and spermatogonia of the rat.

The testis is divided into two compartments: the seminiferous tubules and the interstitial tissue. The latter essentially consists of the blood and lymphatic vessels, testosterone-producing Leydig cells, and testicular macrophages. In the exploration of the testicular antiviral defense system, we initially searched for interferon (IFN) production by the seminiferous tubule cells. The site of virus entry into the testis is probably the interstitial compartment; thus, it is important to know whether and how the cells in this compartment are protected against viral infection. In addition, as germ cell precursors (spermatogonia) are only partially protected by the blood-testis barrier, it was important to explore the antiviral capability of these cells. In this study we searched for IFN production by Leydig cells, testicular macrophages, and spermatogonia after exposure to Sendai virus. We also investigated the effect of viral exposure on testosterone production by Leydig cells. Our results show that spermatogonia do not constitutively express IFNs and give a very poor response to the virus. In contrast, testicular macrophages constitutively produced type I IFNs, and this production was markedly stimulated by Sendai virus. Leydig cells produced twice as much type I IFNs as testicular macrophages after viral exposure, and they were the only cells producing both IFNalpha and -gamma, with these IFNs being dramatically induced/ increased in response to exposure to the virus. Furthermore, incubation of Leydig cells with the Sendai virus stimulated testosterone production. In conclusion, this study further establishes the topography of IFN expression within the testis. This allows us to hypothesize that the potential antiviral system represented by Leydig cells and, to a lesser extent, by macrophages plays a key role in protecting both androgen production and spermatogenesis.

Antibody persistence following preexposure regimens of cell-culture rabies vaccines: 10-year follow-up and proposal for a new booster policy.

Subjects (n = 312) received either the human diploid cell rabies vaccine (HDCV) or the purified Vero cell rabies vaccine (PVRV) according to either two-injection (days 0 and 28) or three-injection (days 0, 7, and 28) primary regimens. They received a booster injection at 1 year. Rabies antibody levels were measured after the primary series and the booster and then each year for the next 10 years. The results confirm the superior long-term immunogenicity of the three-injection over the two-injection protocol. HDCV and PVRV in three doses were equally immunogenic. A booster injection at 1 year provides long-term seroconversion (titer > or = 0.5 IU/mL). Antibody titers 2 weeks after the 1-year booster allowed prediction of long-term immunity. Good responders, with titers > or = 30 IU/mL, were protected for at least 10 years. An algorithm for differentiation between good responders and poor responders with respect to vaccine booster strategies is proposed.

The olfactory adenylyl cyclase type 3 is expressed in male germ cells.

Elements of the olfactory pathway, such as receptors, receptor-desensitization machinery, and cyclic nucleotide-gated channels, are expressed in male germ cells. Here we report the expression, in rat testis, of both adenylyl cyclase type 3 (AC3) and the olfactory G protein subunit, G(alpha)olf. Both are expressed in the same sub-population of germ cells, pachytene spermatocytes to spermatids, and in residual bodies. Neither AC3 nor G(alpha)olf was found in Sertoli or in peritubular cells, as shown by Western blotting and immunocytochemical analyses. It thus appears that male germ cells contain all the elements of the signaling cascade present in olfactory cells.

Interferons and interferon-induced antiviral proteins in the testis.

Despite the dramatic development of sexually transmissible diseases, the antiviral capabilities of testicular cells have not yet been explored. Interferons (IFNs) are proteins playing a key role in the antiviral defense system, their activity being mediated by several IFN-induced proteins. In the present study, we have investigated both the expression of IFN and of the three main IFN-induced proteins by isolated testicular cells. The highest responders to a viral stimulation in terms of IFN production are the Leydig and the Sertoli cells, followed by peritubular cells and testicular macrophages, while germ cells are devoid or virtually devoid of IFN and IFN-induced protein expression. Sertoli cells constitutively expressed the three IFN-induced proteins tested, and their levels were greatly increased after exposure to Sendai virus. Peritubular cells were also able to markedly express these three proteins after viral exposure. In conclusion, we hypothesize that, for a virus coming from the blood, the first testicular line of defence is ensured by Leydig cells and testicular macrophages, the second line being ensured by the myoid cells, lining the seminiferous tubules, and by Sertoli cells. These two barriers are probably fundamental in protecting both androgen production and spermatogenesis.

Type I and type II interleukin-1 receptor expression in rat, mouse, and human testes.

Despite clear indications of interleukin-1 (IL-1) action on Sertoli and germ cells, previous studies failed to detect IL-1 receptors (IL-1R) within the seminiferous tubules. Here, we investigated the existence of the type I signaling receptor (IL-1RI) and the type II decoy receptor (IL-1RII) mRNAs within the testis. Polymerase chain reaction analysis showed the presence of both receptor mRNAs in isolated rat, mouse, and human somatic testicular cells (macrophages, Leydig, Sertoli, and peritubular cells). While also present in rat and mouse isolated pachytene spermatocytes and early spermatids, these receptor mRNAs were not found in human germ cells. The distribution of both IL-1R mRNAs was then examined in adult rat and mouse testis using light and electron microscopic in situ hybridization. No IL-1RI signal was detected in rat testis. In mouse testis, we did not find any signal for IL-1RII. In contrast, IL-1RI mRNA was detected in a wide variety of mouse testicular cells. Strong expression was observed in the rete testis area and high expression was seen over the epithelium of the epididymal duct and in interstitial cells, while lower labeling was detected in peritubular and Sertoli cells and in all germ cell types from spermatogonia to early spermatids; no signal was seen in late spermatids. That the IL-IR was also strongly expressed in the interstitium, the rete testis and efferent duct areas, and the epididymis was established using an autoradiography technique. Overall, our study strongly supports the hypothesis that IL-1 is a regulator of testicular function of prime importance.

[Brucellosis among occupationally exposed people: evaluation of immunological tests after vaccination]. / Brucellose en milieu professionnel exposé: évaluation des tests immunologiques après vaccination.

For the evaluation of immunological tests during an epidemiological survey and of vaccination with the PI brucellin vaccine, in an occupationally exposed environment, a sample group of 354 subjects was studied. The vaccinal strategy was based on the outcome of a skin test for hypersensitivity: the PS brucellin test. In this framework, the serological status and evolution of individuals with positive or negative reactions to this test were analysed. Sera were studied using the buffered antigen test, indirect fluorescence immunoassay and Wright's agglutination test, as well as by PACIA and ELISA techniques with assay of IgG, IgA and IgM antibodies. The PS test, which was pivotal in this study, was compared with the lymphoblastic transformation test. One prominent aspect of this evaluation was the establishment of conventional prognostic indices for the PS and serology. The PS is definitely shown to be a convenient, reliable tool for screening. Although it does not generate sensitivity it may modify the serological status of both positive and negative individuals.

[Pre-exposure rabies immunization in occupational exposed milieu. A 5-year prospective and comparative study of immunogenicity]. / Vaccination antirabique préventive en milieu professionnel exposé. Etude prospective et comparative d'immunogénicité sur 5 ans.

Pre-exposure rabies immunization has been the object of numerous immunogenicity studies with cultivated cell vaccines. Several primary immunizations and booster injection schedules have been suggested. The purpose of the present study was to compare simultaneously the immunogenicities of two vaccines at 5 years and those of two primary immunization schedules with a booster injection at 1 year. We compared the vaccine prepared from Vero cell cultures (PVRV) versus the reference vaccine prepared from human diploid cell culture (HDCV). We also compared primary immunization with 2 injections (on days 0 and 28) versus 3 injections (on days 0, 7 and 28). This phase IV study was prospective, randomized and conducted on open cohorts, according to a factorial plan defining four modalities (HDCV 2, HDCV 3, PVRV 2, PVRV 3). The study involved 312 volunteers of both sexes, aged from 15 to 65 years and exposed to rabies by their profession. The vaccines were injected intramuscularly in the deltoid region. Immunogenicity was evaluated by staged titering of neutralizing antibodies, using immunofluorescence. Seroprotection levels and mean geometrical means of titers were compared. The 3 injections schedule proved to be significantly superior to the 2 injections schedule. No difference could be clearly elicited between the two vaccines. The worst results were obtained with PVRV 2, with a 68.3 percent seroprotection rate at five years; with the other modalities this rate was 93.1 percent or more. We therefore recommend the following procedure: primary immunization by 3 injections, with a booster dose at 1 year, particularly when PVRV is used. It seems that the seroprotection obtained in this manner would make it possible to envisage a booster injection every 5 years.

[Brucella vaccination in professionally exposed subjects. Prospective study]. / Vaccination brucellique en milieu professionnel exposé. Etude prospective.

This prospective phase IV study on cohort concerns a vaccine made of the phenol-insoluble fraction of Brucella abortus biotype 1 (B19 strain). Three hundred and three professionally exposed subjects entered the study; 161 out of 182 subjects (88.5 percent) with negative response to an intradermal test for detection of previous contamination accepted to be vaccinated. Booster injections were given 18 and 36 months after vaccination. Local pain was observed after 45.2 percent of injections and moderate systemic reactions after 5 percent of injections. Seropositivity after primary vaccination reached 80 percent. The booster injection, justified by a major decrease of this rate after 18 months, gave exactly the same response of the thymo-independent type. This vaccinal schedule did not result in detectable hypersensitivity. The clinical effectiveness of the vaccine could not be evaluated accurately because of the insufficient number of subjects. The possibility of subclinical infection in vaccinated subjects calls for wider comparative studies of vaccinated versus non-vaccinated subjects.

Raynaud's phenomenon in chain saw users. Hot and cold finger systolic pressures and nailfold capillary findings.

To gain insight into the physiopathology of Raynaud's phenomenon of occupational origin, finger systolic pressures under heat and cold, and results of nailfold capillary microscopy, were examined in 29 lumberjacks with Raynaud's phenomenon vibration syndrome (pathological group) and 24 lumberjacks without it (non-pathological group), and compared with the same values in 26 healthy matched manual workers not using a vibrating tool (controls). Vibration syndrome physiopathology seemed multifactorial, combining 5 features: a rise in brachial diastolic and systolic pressures in the pathological group compared with the two other groups. In lumberjacks with Raynaud's phenomenon, these rises seemed to be acquired, since they were not found when the workers were engaged; a reduction in the number of nailfold capillaries (9.4 +/- 2 per mm in the pathological group vs 11 +/- 2.5 in the controls, P less than 0.025); a rise in the brachial digital systolic gradient (P less than 0.025) in the pathological versus the non-pathological lumberjack group abnormal cold vascular tone, since at 15 degrees C finger systolic pressures in the pathological group were lower than pressures in both the control and non-pathological groups (P less than 0.05 and P less than 0.01, respectively), and at 10 degrees C, they were lower in the pathological than in the control group (P less than 0.01); Within the pathological group, individual paired comparisons between the most and least symptomatic finger revealed a rise in the cold vascular tone, and a reduction in the number of nailfold capillaries in the most symptomatic finger compared to the least symptomatic finger.(ABSTRACT TRUNCATED AT 250 WORDS)

[Raynaud's syndrome in lumberjacks using chain saws. Epidemiology, clinical and capillaroscopic findings]. / Le syndrome de Raynaud des bûcherons utilisant une scie tronçonneuse. Epidémiologie, clinique et capillaroscopie.

The overall incidence of Raynaud's syndrome in lumberjacks using a mechanic chain saw in France is at least 45%; workers exposed to the risk for more than 3 years have an incidence of about 60%. Vibrations are probably directly responsible for the disease, while among the other favorizing factors the different winter climatic conditions do not appear to be relevant, and this is the case with conventional vascular risk factors, apart perhaps for hypertension. A history of injury to hands is significantly more frequent in affected subjects possibly related to a relative digital cutaneous hypo-esthesia. Capillaroscopy shows organic microangiopathies with reduction in number of nail-bed capillaries and functional angiopathies of arteries of hand in the form of abnormal spasm induced by cold. Technical progress by the use of chain saws has markedly reduced incidence of this occupational disease, but in France it would appear that only modifications in working conditions of lumberjacks could reduce the incidence of the disease.