Epidemiology and prophylaxis of rabies in humans in France: evaluation and perspectives of a twenty-five year surveillance programme.

The National Reference Centre for Rabies (NRC) was created at the Pasteur Institute after the fox epizootic reached the French territory. The missions of the NRC include, among others, the surveillance of rabies cases in humans and rabies post-exposure prophylaxis (PEP) treatments. The surveillance has been effective since 1982. A Bulletin on the Epidemiology and the Prophylaxis of Rabies in Humans in France is published every year. This Bulletin is now available on the Internet for Human Health and Veterinary national and local Authorities. Since 2005, data is collected with new software, Voozanoo, directly via the Internet. Twenty cases of rabies in humans have been reported since 1970. There were no indigenously acquired cases. The number of PEP treatments peaked in 1990, when the number of cases in the wild fauna was at its acme. Following the decrease of rabies cases in the wild fauna, PEP decreased by 60%. Nevertheless, about4,000 PEP treatments are still carried out. These patients have been exposed to bats or to rabid animals illegally introduced onto the French territory, or during a stay in rabies enzootic countries, or to unobservable animals. The study of this database leads to a number of conclusions: canine variants acquired directly in canine enzootic areas, that are translocated, or acquired through iatrogenic exposure, are responsible for the majority of cases; bats appear to be an increasing source of exposure; PEP surveillance is of utmost importance to monitor and to improve the quality of case management.

[Human rabies in France in 2004: update and management]. / La rage humaine en France en 2004: état des lieux et prise en charge.

Twenty people died of rabies in France between 1970 and 2003 (compared to 55,000 yearly worldwide), 80% on returning from Africa. Dogs were the contaminating animals in 90% of the cases and children were the most common victims. The last instance of rabies in a native French animal was reported in 1998. However the illegal importation of animals still poses a risk. The disease is transmitted by saliva, even before the appearance of clinical symptoms, through a bite, scratch, or licks of mucous membranes or broken skin. Person-to-person transmission has only been observed in cases of grafts (cornea). The mean incubation time of 1 to 3 months is long enough to allow passive immunization and vaccination. After its onset, the disease presents as encephalitis or a paralytic syndrome the outcome of which is always fatal. Clinical diagnosis may be difficult in the early stages of the disease. If rabies is suspected, the National Reference Centre is responsible for the sampling and proper transportation of these samples so as to ensure assessment results within 5 days. If stringent hygiene rules are complied to, there is no risk of contamination for those in close contact. Vaccination, which is performed in official rabies centers, is only performed after a diagnosis based on laboratory evidence, and solely for exposed persons or those for whom a reliable history cannot be established (children under 6 years). Prevention is based on information. People traveling abroad, particularly to Africa, are warned not to approach unknown animals (especially dogs) nor to try to import them, and are advised to comply with vaccinal recommendations for travelers, particularly for toddlers.

Human rabies prophylactics: the French experience.

In 1968, fox rabies was introduced on the French territory, in the Moselle department and from that time, spread southwards and westwards from the French-German border at the speed of 40 km per year. Consequently, a program aimed at controlling and eradicating the disease was carried out. Collaboration between human and veterinary medicine has been the key of the success of this program. In 2001, rabies in terrestrial animals was eradicated from France, while no indigenous human rabies case had been reported. Meanwhile, post-exposure treatments (PET) had been closely monitored. Data on rabies cases in animals, rabies cases in humans, PET, surveillance of exposures to baits and oral vaccines for the wild fauna, and exposures outside the French territory will be successively considered and discussed.

[Rabies is a risk for travelling children]. / Le risque de rage chez l'enfant qui voyage.

Rabies remains a dreadful disease which kills about 50,000 people per year, mostly in Asia, Africa, South America and Central Europe. Between 30% an 50% of the victims are young children. Modern rabies vaccines are safe and immunogenic. Therefore parents must be informed on the risk of rabies, and pre-exposure vaccination must be performed for children traveling often or for periods longer than one month in canine enzootic countries. Post-exposure treatment must be initiated without delay with modern vaccines wherever available, according to approved schedules. Pre-exposure vaccination is particularly useful in remote places where modern vaccines and immunoglobulins are not readily available.

Intravitam diagnosis of human rabies by PCR using saliva and cerebrospinal fluid.

An optimized reverse transcription (RT)-PCR protocol for the intravitam detection of rabies virus genomic RNA was tested with clinical samples obtained from 28 patients suspected of having rabies, 9 of whom were confirmed to have had rabies by postmortem examination. RT-PCR using saliva combined with an immunofluorescence assay performed with skin biopsy samples allowed detection of rabies in the nine patients.

Immunogenicity and safety in adults of a new chromatographically purified Vero-cell rabies vaccine (CPRV): a randomized, double-blind trial with purified Vero-cell rabies vaccine (PVRV).

Recent improvements in chromatographic purification procedures have made it possible to develop a new chromatographically purified rabies vaccine (CPRV) by further purifying the current rabies vaccine prepared from Vero-cell culture (Verorab; Pasteur Mérieux Connaught). The immunogenicity and safety of primary immunization, followed by a booster at one year, with CPRV was compared to that of the purified Vero cell vaccine (PVRV) in a randomized, double-blind study carried out at four veterinary schools in France. A total of 330 healthy, male and female, first-year veterinary students, aged at least 18 years and who required pre-exposure rabies prophylaxis, were enrolled in this study. Included subjects were randomly assigned either CPRV (n = 163) or PVRV (n = 167) to be given as a primary immunization series of three intramuscular injections (D0, D7, D28), followed by a booster after 1 year (D365). Blood samples for serological analysis were taken at D0 (before first injection), D28, D42, D180, D365 (before booster) and D379. All subjects developed a strong immune response to the primary series, and at D42, all subjects had seroconverted for rabies neutralizing antibody (serum titre > or = 0.5 IU/ml). The rabies virus-neutralizing antibody GMT value at D42 in the CPRV group (23.0 IU/ml) was non-inferior to that in the PVRV group (29.6 IU/ml), according to a one-sided non-inferiority test. While antibody titres tended to decrease over the period of follow-up, at D365 (before booster), 97.5% subjects in the CPRV group and 98.8% of subjects in the PVRV group remained seroconverted. After booster, although the rabies antibody GMT value in the CPRV group was lower than that in the PVRV group, all subjects in both groups were seroconverted, and the difference is probably not clinically important. The incidence of local and systemic reactions tended to decrease with each dose during the primary immunization series, followed by a slight increase after booster (significant time-effect in an exploratory logistic regression analysis). Although mild or moderate local reactions tended to be more frequent after injection with CPRV compared to PVRV, systemic reactions were reported less often (significant group-effects in exploratory logistic regression analyses). One serious adverse event possibly related to vaccine occurred during this study (severe asthenia after the third dose of PVRV). This comparative study in healthy young adults demonstrates that the new chromatographically purified rabies vaccine is as immunogenic as PVRV, and seems to be associated with fewer systemic reactions.

[Human contamination by baits for vaccinating foxes against rabies in France]. / Contamination de personnes par des appâts vaccins après les campagnes de vaccination des renards contre la rage en France.

During 1992 and 1993, 4.4 million of baits have been distributed in France over 121,381 km2 for vaccinating foxes against rabies. Phone calls and visits addressed to the local veterinary authorities and to the centres for human antirabies treatment have been recorded according to an appropriate questionnaire. 70 persons declared to have found and sometimes to have touch a bait, 38 of them received a antirabies treatment. Only 9 children (less than 10 year old) handled a bait. Activities that led to find a bait have been: walking in the countryside or hunting (50% of cases), gardening or playing in the garden or near home (35%) and farming (13%). Often dogs were the first to discover the baits and led to a contact of humans with the vaccine in 54% of cases. No casualty occurred. The frequency of these reports decrease by 80% during the period which is considered to be the result of a better information and awareness of the public.

Rabies encephalitis in a patient with AIDS: a clinicopathological study.

A 46-year-old man was bitten by a dog in Mali; anti-rabies vaccination was incomplete. Three months later he was admitted to hospital with fever and diarrhea. Human immunodeficiency virus (HIV) serology was positive and CD4 count was 70/mm3. His status worsened rapidly with confusion hydrophobia and hypersialorrhea. Despite anti-rabies serotherapy and vaccination, he died suddenly 12 days after admission. Immunofluorescence on cerebral tissue samples established rabies encephalitis. Neuropathology showed mild encephalitis with occasional Babès nodules and rare perivascular mononuclear cuffs. Intraneuronal Negri inclusion bodies were remarkably diffuse and abundant. They were clearly demonstrated by immunocytochemistry and electron microscopy. Apoptotic neurons were identified in the brain stem and hippocampus in the vicinity of inflammatory foci. In contrast, apoptosis could not be demonstrated in non-inflammatory areas, even where Negri bodies were numerous. There was no associated HIV encephalitis or opportunistic infection. The occurrence of rabies encephalitis in AIDS represents a random association, but is probably not exceptional as rabies is endemic in many countries and the AIDS epidemic is spreading worldwide. In this case, although the incubation duration and clinical presentation were comparable to those in classical rabies the T-cell-mediated immunosuppression may account for the weak inflammatory reaction and unusually abundant viral multiplication. This observation confirms that all those at risk for rabies, particularly immunocompromised patients, should receive complete anti-rabies treatment including vaccines and specific immunoglobulins, as soon as possible after infection.

[Immunoprophylaxis of rabies: current recommendations]. / L'immuno-prophylaxie de la rage: actualisation des recommandations.

Pre-exposure rabies vaccination should comprise 3 injections (day 0, day 7, day 28) followed by boosters 1 year later then every 5 years. Populations who are particularly exposed due to occupation, regular contact with animals in endemic areas during leisure activities or holidays should be vaccinated, especially if access to post-exposure treatment is difficult. Post-exposure treatment should comprise 5 injections (day 0, day 3, day 7, day 14, day 28) which must be given with specific immunoglobulins on day 0 if there are penetrating wounds. In persons whose prior vaccination status is well-documented and correctly maintained, post-exposure treatment may be limited to 2 injections on day 0 and day 3. The vaccine is given is intramuscular injection in the deltoid region. Immunoglobulins are used at the dose of 20 IU/kg for human immunoglobulins and at 40 IU/kg for horse immunoglobulins. The injections are infiltrated around the lesions and the remaining quantity injected in the gluteus muscle. Seroconversion must be monitored by assaying neutralizing antibodies (titre > or = 0.5 IU/ml with the RFFI Test) in vaccinated populations who regularly exposed. Monitoring can also be useful after post-exposure treatment in certain specific cases (immunosuppressed subjects, treatment protocol incorrectly or incompletely applied). An antibody titre under 0.5 IU/ml requires an immediate vaccine injection.

[Vaccination against hepatitis B virus at the Lyon Pasteur Institute. A seven-year evaluation]. / Vaccination contre le virus de l'hépatite B à l'Institut Pasteur de Lyon. Bilan de sept ans.

Results of immunization against hepatitis B among Pasteur Institute staff members are reported. Prior to immunization, 439 subjects were tested for hepatitis B virus (HBV) markers, including HBs antigen, anti-HBs antibody, and anti-HBc antibody (Ausria, Ausab, Corab assays; Abbott). Forty-seven subjects tested positive for anti-HBs antibody. 317 subjects negative for all the HBs markers studied were given three intramuscular doses of Hevac B (Pasteur vaccins) at one-month intervals. Anti-HBs antibodies were assayed after the third injection with the following results: mean titer, 1,454 mIU/ml, standard deviation, 5,349 mIU/ml, and range, 4 to 41,100 mIU/ml. Anti-HBs titers above 10 mIU/ml were found in 879.4% of subjects. Non-responders and weak responders (anti-HBs titer under 10 mIU/ml) were given a fourth dose of vaccine. Ultimately, after the last (third of fourth) injection 97.6% of subjects had protective antibody titers. No case of HBV infection was seen during the seven-year follow-up period.

Combined tetanus-rabies vaccination.

Studies in mice have shown that Calcium Phosphate adsorbed tetanus toxoid (IPADT) can be used as a vehicle for freezedried rabies vaccine. Trials were undertaken in human volunteers and patients receiving a post-exposure treatment using the same vaccines to evaluate tolerance and antibody response to both vaccines.