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International audience ; As in previous years, the European Union Reference Laboratory (EURL) for rabies organised in 2018 an Inter-laboratory trial (ILT) on rabies diagnosis. Contrarily to past years, the 2018 ILT did not aim to evaluate the performance of participating laboratories, but the technical performance of new rapid tests. Two lateral Flow Assays (LFA), namely the Anigen® and the CDIA™ Rabies Virus Antigen Rapid Test" (commercialized by Bionote and Creative Diagnostics Cie respectively), were evaluated together with the Fluorescent Antibody Test (FAT). One panel of virus samples (including RABV as well as EBLV1a, EBLV-1b, and EBLV2 strains) was sent to participating laboratories to compare results obtained with these different techniques.The study revealed that the FAT provided a good agreement toward expected results for both negative/positive samples (99.1%). The Anigen® test produced similar results to the FAT, with only one false negative result (0.5%) reported by all participants and a concordance of 100% for all but one sample demonstrating a good inter-laboratory reproducibility of the Anigen® batch. The CDIA™ test produced reproducible results for Rabies Virus (RABV) samples only. However, it hardly detected the Bokeloh Bat Lyssavirus (BBLV) and the European Bat Lyssaviruses types 1b and 2 (EBLV-1b and EBLV-2) in most laboratories resulting in a moderate inter-laboratory concordance (58.4%–82.7%) for these lyssaviruses.The two LFAs provided reliable and reproducible results on all RABV samples (100%) but lead to heterogeneous performances with other lyssaviruses leading to different levels of diagnostic/analytical sensitivity, specificity. The study confirmed that LFAs should be used with caution and that their validation are of upmost importance before any use in laboratories.

International audience ; As in previous years, the European Union Reference Laboratory (EURL) for rabies organised in 2018 an Inter-laboratory trial (ILT) on rabies diagnosis. Contrarily to past years, the 2018 ILT did not aim to evaluate the performance of participating laboratories, but the technical performance of new rapid tests. Two lateral Flow Assays (LFA), namely the Anigen® and the CDIA™ Rabies Virus Antigen Rapid Test" (commercialized by Bionote and Creative Diagnostics Cie respectively), were evaluated together with the Fluorescent Antibody Test (FAT). One panel of virus samples (including RABV as well as EBLV1a, EBLV-1b, and EBLV2 strains) was sent to participating laboratories to compare results obtained with these different techniques.The study revealed that the FAT provided a good agreement toward expected results for both negative/positive samples (99.1%). The Anigen® test produced similar results to the FAT, with only one false negative result (0.5%) reported by all participants and a concordance of 100% for all but one sample demonstrating a good inter-laboratory reproducibility of the Anigen® batch. The CDIA™ test produced reproducible results for Rabies Virus (RABV) samples only. However, it hardly detected the Bokeloh Bat Lyssavirus (BBLV) and the European Bat Lyssaviruses types 1b and 2 (EBLV-1b and EBLV-2) in most laboratories resulting in a moderate inter-laboratory concordance (58.4%–82.7%) for these lyssaviruses.The two LFAs provided reliable and reproducible results on all RABV samples (100%) but lead to heterogeneous performances with other lyssaviruses leading to different levels of diagnostic/analytical sensitivity, specificity. The study confirmed that LFAs should be used with caution and that their validation are of upmost importance before any use in laboratories.

International audience ; Rabies diagnosis proficiency tests on animal specimens using four techniques (FAT, RTCIT, conventional RT-PCR and real-time RT-PCR) were organised over 10 years (2009–2019). Seventy-three laboratories, of which 59% were from Europe, took part. As the panels were prepared with experimentally-infected samples, the error rate of laboratories on positive and negative samples was accurately estimated. Based on fitted values produced by mixed modelling including the variable "laboratory" as a random variable to take into account the longitudinal design of our dataset, the technique that provided the most concordant results was conventional RT-PCR (99.3%; 95% CI 99.0–99.6), closely followed by FAT (99.1%; 95% CI 98.7–99.4), real-time RT-PCR (98.7%; 95% CI 98.1–99.3) and then RTCIT (96.8%; 95% CI 95.8–97.7). We also found that conventional RT-PCR provided a better diagnostic sensitivity level (99.3% ±4.4%) than FAT (98.7% ±1.6%), real-time RT-PCR (97.9% ±0.8%) and RTCIT (95.3% ±5.1%). Regarding diagnostic specificity, RTCIT was the most specific technique (96.4% ±3.9%) followed closely by FAT (95.6% ±3.8%), real-time RT-PCR (95.0% ±1.8%) and conventional RT-PCR (92.9% ±0.5%). Due to multiple testing of the samples with different techniques, the overall diagnostic conclusion was also evaluated, and found to reach an inter-laboratory concordance level of 99.3%. The concordance for diagnostic sensitivity was 99.6% ±2.0% and for diagnostic specificity, 98.0% ±8.5%. Molecular biology techniques were, however, found to be less specific than expected. The potential reasons for such findings are discussed herein. The regular organisation of performance tests has contributed to an increase in the performance of participating laboratories over time, demonstrating the benefits of such testing. Maintaining a high-quality rabies diagnosis capability on a global scale is key to achieving the goal of eliminating dog-mediated human rabies deaths. The regular organisation of exercises on each continent using ...

International audience ; Rabies diagnosis proficiency tests on animal specimens using four techniques (FAT, RTCIT, conventional RT-PCR and real-time RT-PCR) were organised over 10 years (2009–2019). Seventy-three laboratories, of which 59% were from Europe, took part. As the panels were prepared with experimentally-infected samples, the error rate of laboratories on positive and negative samples was accurately estimated. Based on fitted values produced by mixed modelling including the variable "laboratory" as a random variable to take into account the longitudinal design of our dataset, the technique that provided the most concordant results was conventional RT-PCR (99.3%; 95% CI 99.0–99.6), closely followed by FAT (99.1%; 95% CI 98.7–99.4), real-time RT-PCR (98.7%; 95% CI 98.1–99.3) and then RTCIT (96.8%; 95% CI 95.8–97.7). We also found that conventional RT-PCR provided a better diagnostic sensitivity level (99.3% ±4.4%) than FAT (98.7% ±1.6%), real-time RT-PCR (97.9% ±0.8%) and RTCIT (95.3% ±5.1%). Regarding diagnostic specificity, RTCIT was the most specific technique (96.4% ±3.9%) followed closely by FAT (95.6% ±3.8%), real-time RT-PCR (95.0% ±1.8%) and conventional RT-PCR (92.9% ±0.5%). Due to multiple testing of the samples with different techniques, the overall diagnostic conclusion was also evaluated, and found to reach an inter-laboratory concordance level of 99.3%. The concordance for diagnostic sensitivity was 99.6% ±2.0% and for diagnostic specificity, 98.0% ±8.5%. Molecular biology techniques were, however, found to be less specific than expected. The potential reasons for such findings are discussed herein. The regular organisation of performance tests has contributed to an increase in the performance of participating laboratories over time, demonstrating the benefits of such testing. Maintaining a high-quality rabies diagnosis capability on a global scale is key to achieving the goal of eliminating dog-mediated human rabies deaths. The regular organisation of exercises on each continent using selected local strains to be tested according to the local epidemiological situation is one factor that could help increase reliable diagnosis worldwide. Rabies diagnosis capabilities could indeed be enhanced by providing adequate and sustainable proficiency testing on a large scale and in the long term

AbstractFrance has been rabies‐free among nonflying mammals since 2001. Despite this status, the rabies virus has been introduced several times through noncommercial pet movements, posing a threat of infection by this 100%‐lethal zoonosis among local animal and human populations. To quantify the risk of rabies being introduced through worldwide noncommercial dog and cat movements, we performed a quantitative risk assessment using stochastic scenario tree modeling. The mean annual probability of at least one rabies introduction incident was 0.35 (median: 0.24, 90% prediction interval (PI) [0.04; 0.98]) and the mean annual number of rabies‐infected pets introduced through pet movements was 0.96 (median: 0.27, 90% PI [0.04; 3.88]). These results highlight a nonnegligible, even high risk due to the associated consequences of such events. In alternative scenario testing, preventive anti‐rabies vaccination proved to be an effective measure since removing the vaccination requirement led to a > 15‐fold increase in risk. The serological testing requirement had less of an effect (approximately two‐fold increase when removed) and the posttest waiting period to ensure that antibodies were not linked to an infection had a negligible effect. Any change in pet owner compliance, especially regarding vaccination, could have a major impact on the risk. This study also shows that reinforced border control staff training could be more effective in reducing risk than more frequent checks. These results provide quantitative data for assessing the probability of the rabies virus entering France, and could help policymakers decrease this risk in rabies‐free areas.

International audience ; In France, apparently healthy dogs and cats that bite humans must undergo an observation period of 15 days with three veterinary visits to ascertain that they remain healthy, indicating that no zoonotic transmission of rabies virus occurred via salivary presymptomatic excretion. This surveillance protocol is mandatory for all pets that have bitten humans, despite France's rabies-free status in non-flying mammals (i.e., a very low rabies risk). In this context, we aimed to perform a benefit–risk assessment of the existing regulatory surveillance protocol of apparently healthy biting animals, as well as alternative surveillance protocols. A scenario-tree modelling approach was used to consider the possible successions of events between a dog or cat bite and a human death attributed to either rabies or to lethal harm associated with the surveillance protocol (e.g., lethal traffic accidents when traveling to veterinary clinics or anti-rabies centers). The results demonstrated that the current French surveillance protocol was not beneficial, as more deaths were generated (traffic accidents) than avoided (by prompt post-exposure prophylaxis administration). We showed here that less stringent risk-based surveillance could prove more appropriate in a French context. The results in this study could allow policy-makers to update and optimize rabies management legislation.

International audience ; In France, apparently healthy dogs and cats that bite humans must undergo an observation period of 15 days with three veterinary visits to ascertain that they remain healthy, indicating that no zoonotic transmission of rabies virus occurred via salivary presymptomatic excretion. This surveillance protocol is mandatory for all pets that have bitten humans, despite France's rabies-free status in non-flying mammals (i.e., a very low rabies risk). In this context, we aimed to perform a benefit–risk assessment of the existing regulatory surveillance protocol of apparently healthy biting animals, as well as alternative surveillance protocols. A scenario-tree modelling approach was used to consider the possible successions of events between a dog or cat bite and a human death attributed to either rabies or to lethal harm associated with the surveillance protocol (e.g., lethal traffic accidents when traveling to veterinary clinics or anti-rabies centers). The results demonstrated that the current French surveillance protocol was not beneficial, as more deaths were generated (traffic accidents) than avoided (by prompt post-exposure prophylaxis administration). We showed here that less stringent risk-based surveillance could prove more appropriate in a French context. The results in this study could allow policy-makers to update and optimize rabies management legislation.

In France, apparently healthy dogs and cats that bite humans must undergo an observation period of 15 days with three veterinary visits to ascertain that they remain healthy, indicating that no zoonotic transmission of rabies virus occurred via salivary presymptomatic excretion. This surveillance protocol is mandatory for all pets that have bitten humans, despite France's rabies-free status in non-flying mammals (i.e., a very low rabies risk). In this context, we aimed to perform a benefit–risk assessment of the existing regulatory surveillance protocol of apparently healthy biting animals, as well as alternative surveillance protocols. A scenario-tree modelling approach was used to consider the possible successions of events between a dog or cat bite and a human death attributed to either rabies or to lethal harm associated with the surveillance protocol (e.g., lethal traffic accidents when traveling to veterinary clinics or anti-rabies centers). The results demonstrated that the current French surveillance protocol was not beneficial, as more deaths were generated (traffic accidents) than avoided (by prompt post-exposure prophylaxis administration). We showed here that less stringent risk-based surveillance could prove more appropriate in a French context. The results in this study could allow policy-makers to update and optimize rabies management legislation.

International audience ; In France, apparently healthy dogs and cats that bite humans must undergo an observation period of 15 days with three veterinary visits to ascertain that they remain healthy, indicating that no zoonotic transmission of rabies virus occurred via salivary presymptomatic excretion. This surveillance protocol is mandatory for all pets that have bitten humans, despite France's rabies-free status in non-flying mammals (i.e., a very low rabies risk). In this context, we aimed to perform a benefit–risk assessment of the existing regulatory surveillance protocol of apparently healthy biting animals, as well as alternative surveillance protocols. A scenario-tree modelling approach was used to consider the possible successions of events between a dog or cat bite and a human death attributed to either rabies or to lethal harm associated with the surveillance protocol (e.g., lethal traffic accidents when traveling to veterinary clinics or anti-rabies centers). The results demonstrated that the current French surveillance protocol was not beneficial, as more deaths were generated (traffic accidents) than avoided (by prompt post-exposure prophylaxis administration). We showed here that less stringent risk-based surveillance could prove more appropriate in a French context. The results in this study could allow policy-makers to update and optimize rabies management legislation.

International audience ; In France, apparently healthy dogs and cats that bite humans must undergo an observation period of 15 days with three veterinary visits to ascertain that they remain healthy, indicating that no zoonotic transmission of rabies virus occurred via salivary presymptomatic excretion. This surveillance protocol is mandatory for all pets that have bitten humans, despite France's rabies-free status in non-flying mammals (i.e., a very low rabies risk). In this context, we aimed to perform a benefit–risk assessment of the existing regulatory surveillance protocol of apparently healthy biting animals, as well as alternative surveillance protocols. A scenario-tree modelling approach was used to consider the possible successions of events between a dog or cat bite and a human death attributed to either rabies or to lethal harm associated with the surveillance protocol (e.g., lethal traffic accidents when traveling to veterinary clinics or anti-rabies centers). The results demonstrated that the current French surveillance protocol was not beneficial, as more deaths were generated (traffic accidents) than avoided (by prompt post-exposure prophylaxis administration). We showed here that less stringent risk-based surveillance could prove more appropriate in a French context. The results in this study could allow policy-makers to update and optimize rabies management legislation.

International audience ; In France, apparently healthy dogs and cats that bite humans must undergo an observation period of 15 days with three veterinary visits to ascertain that they remain healthy, indicating that no zoonotic transmission of rabies virus occurred via salivary presymptomatic excretion. This surveillance protocol is mandatory for all pets that have bitten humans, despite France's rabies-free status in non-flying mammals (i.e., a very low rabies risk). In this context, we aimed to perform a benefit–risk assessment of the existing regulatory surveillance protocol of apparently healthy biting animals, as well as alternative surveillance protocols. A scenario-tree modelling approach was used to consider the possible successions of events between a dog or cat bite and a human death attributed to either rabies or to lethal harm associated with the surveillance protocol (e.g., lethal traffic accidents when traveling to veterinary clinics or anti-rabies centers). The results demonstrated that the current French surveillance protocol was not beneficial, as more deaths were generated (traffic accidents) than avoided (by prompt post-exposure prophylaxis administration). We showed here that less stringent risk-based surveillance could prove more appropriate in a French context. The results in this study could allow policy-makers to update and optimize rabies management legislation.

International audience ; In France, apparently healthy dogs and cats that bite humans must undergo an observation period of 15 days with three veterinary visits to ascertain that they remain healthy, indicating that no zoonotic transmission of rabies virus occurred via salivary presymptomatic excretion. This surveillance protocol is mandatory for all pets that have bitten humans, despite France's rabies-free status in non-flying mammals (i.e., a very low rabies risk). In this context, we aimed to perform a benefit–risk assessment of the existing regulatory surveillance protocol of apparently healthy biting animals, as well as alternative surveillance protocols. A scenario-tree modelling approach was used to consider the possible successions of events between a dog or cat bite and a human death attributed to either rabies or to lethal harm associated with the surveillance protocol (e.g., lethal traffic accidents when traveling to veterinary clinics or anti-rabies centers). The results demonstrated that the current French surveillance protocol was not beneficial, as more deaths were generated (traffic accidents) than avoided (by prompt post-exposure prophylaxis administration). We showed here that less stringent risk-based surveillance could prove more appropriate in a French context. The results in this study could allow policy-makers to update and optimize rabies management legislation.

International audience ; BACKGROUND: Domestic carnivores can introduce rabies into disease-free countries or areas if they are incubating the disease and transported during the pre-symptomatic period. For pets moved into the European Union, the European Commission decided to establish a system of community approval of laboratories willing to carry out the rabies serological controls to guarantee an effective control system. As the specific institute to coordinate the approval of the laboratories, designated by the European Commission in 2000, our laboratory organizes annual proficiency tests (PT) for laboratories already agreed or willing to be agreed to perform rabies serological controls (by detecting rabies virus neutralizing antibodies only) in the frame of international trade.METHODOLOGY/PRINCIPAL FINDINGS: The assessment criteria of this PT rely on the analysis of the specificity and the intra-laboratory consistency. The approach used to evaluate the degree of laboratory consistency is based on the use of compiled data obtained from previous PT campaigns, and is measured by the quality of a regression model. By using historical data for calculating assigned values and associated standard deviations, instead of values obtained from only one campaign, they became robust without any additional statistical treatment. In the present paper, more than 800 historical values were compiled for each of the regression parameters.CONCLUSIONS/SIGNIFICANCE: Since the beginning of these PT schemes in 1999, the overall percentage of failing laboratories remained stable over the years (4.1%) while the number of participants increased to 79 in 2018. This highlighted the robustness and the consistency of the statistical analyses used to assess the laboratory's performance over the years. The improvements carried out and the consistency of our statistical analyses have resulted in the compliance of the rabies serology PT with the ISO/IEC 17043 and ISO 13528:2015 International Standards.

International audience ; BACKGROUND: Domestic carnivores can introduce rabies into disease-free countries or areas if they are incubating the disease and transported during the pre-symptomatic period. For pets moved into the European Union, the European Commission decided to establish a system of community approval of laboratories willing to carry out the rabies serological controls to guarantee an effective control system. As the specific institute to coordinate the approval of the laboratories, designated by the European Commission in 2000, our laboratory organizes annual proficiency tests (PT) for laboratories already agreed or willing to be agreed to perform rabies serological controls (by detecting rabies virus neutralizing antibodies only) in the frame of international trade.METHODOLOGY/PRINCIPAL FINDINGS: The assessment criteria of this PT rely on the analysis of the specificity and the intra-laboratory consistency. The approach used to evaluate the degree of laboratory consistency is based on the use of compiled data obtained from previous PT campaigns, and is measured by the quality of a regression model. By using historical data for calculating assigned values and associated standard deviations, instead of values obtained from only one campaign, they became robust without any additional statistical treatment. In the present paper, more than 800 historical values were compiled for each of the regression parameters.CONCLUSIONS/SIGNIFICANCE: Since the beginning of these PT schemes in 1999, the overall percentage of failing laboratories remained stable over the years (4.1%) while the number of participants increased to 79 in 2018. This highlighted the robustness and the consistency of the statistical analyses used to assess the laboratory's performance over the years. The improvements carried out and the consistency of our statistical analyses have resulted in the compliance of the rabies serology PT with the ISO/IEC 17043 and ISO 13528:2015 International Standards.

International audience ; The elimination of rabies transmitted by Classical Rabies Virus (RABV) in the European Union (EU) is now in sight. Scientific advances have made it possible to develop oral vaccination for wildlife by incorporating rabies vaccines in baits for foxes. At the start of the 1980s, aerial distribution of vaccine baits was tested and found to be a promising tool. The EU identified rabies elimination as a priority, and provided considerable financial and technical resources to the infected EU Member States, allowing regular and large-scale rabies eradication programs based on aerial vaccination. The EU also provides support to non-EU countries in its eastern and south eastern borders. The key elements of the rabies eradication programs are oral rabies vaccination (ORV), quality control of vaccines and control of their distribution, rabies surveillance and monitoring of the vaccination effectiveness. EU Member States and non-EU countries with EU funded eradication programs counted on the technical support of the rabies subgroup of the Task Force for monitoring disease eradication and of the EU Reference Laboratory (EURL) for rabies. In 2018, eight rabies cases induced by classical rabies virus RABV (six in wild animals and two in domestic animals) were detected in three EU Member States, representing a sharp decrease compared to the situation in 2010, where there were more than 1500 cases in nine EU Member States. The goal is to reach zero cases in wildlife and domestic animals in the EU by 2020, a target that now seems achievable.