Genomic Diversity and Evolution of the Lyssaviruses

Lyssaviruses are RNA viruses with single-strand, negative-sense genomes responsible for rabies-like diseases in mammals. To date, genomic and evolutionary studies have most often utilized partial genome sequences, particularly of the nucleoprotein and glycoprotein genes, with little consideration of genome-scale evolution. Herein, we report the first genomic and evolutionary analysis using complete genome sequences of all recognised lyssavirus genotypes, including 14 new complete genomes of field isolates from 6 genotypes and one genotype that is completely sequenced for the first time. In doing so we significantly increase the extent of genome sequence data available for these important viruses. Our analysis of these genome sequence data reveals that all lyssaviruses have the same genomic organization. A phylogenetic analysis reveals strong geographical structuring, with the greatest genetic diversity in Africa, and an independent origin for the two known genotypes that infect European bats. We also suggest that multiple genotypes may exist within the diversity of viruses currently classified as ‘Lagos Bat’. In sum, we show that rigorous phylogenetic techniques based on full length genome sequence provide the best discriminatory power for genotype classification within the lyssaviruses

Rabies, Still Neglected after 125 Years of Vaccination

International audienceno abstrac

Temporal Dynamics of European Bat Lyssavirus Type 1 and Survival of Myotis myotis Bats in Natural Colonies

Many emerging RNA viruses of public health concern have recently been detected in bats. However, the dynamics of these viruses in natural bat colonies is presently unknown. Consequently, prediction of the spread of these viruses and the establishment of appropriate control measures are hindered by a lack of information. To this aim, we collected epidemiological, virological and ecological data during a twelve-year longitudinal study in two colonies of insectivorous bats (Myotis myotis) located in Spain and infected by the most common bat lyssavirus found in Europe, the European bat lyssavirus subtype 1 (EBLV-1). This active survey demonstrates that cyclic lyssavirus infections occurred with periodic oscillations in the number of susceptible, immune and infected bats. Persistence of immunity for more than one year was detected in some individuals. These data were further used to feed models to analyze the temporal dynamics of EBLV-1 and the survival rate of bats. According to these models, the infection is characterized by a predicted low basic reproductive rate (R0 = 1.706) and a short infectious period (D = 5.1 days). In contrast to observations in most non-flying animals infected with rabies, the survival model shows no variation in mortality after EBLV-1 infection of M. myotis. These findings have considerable public health implications in terms of management of colonies where lyssavirus-positive bats have been recorded and confirm the potential risk of rabies transmission to humans. A greater understanding of the dynamics of lyssavirus in bat colonies also provides a model to study how bats contribute to the maintenance and transmission of other viruses of public health concern

More Accurate Insight into the Incidence of Human Rabies in Developing Countries through Validated Laboratory Techniques

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Development of broad-spectrum human monoclonal antibodies for rabies post-exposure prophylaxis

Currently available rabies post-exposure prophylaxis (PEP) for use in humans includes equine or human rabies immunoglobulins (RIG). The replacement of RIG with an equally or more potent and safer product is strongly encouraged due to the high costs and limited availability of existing RIG. In this study, we identified two broadly neutralizing human monoclonal antibodies that represent a valid and affordable alternative to RIG in rabies PEP. Memory B cells from four selected vaccinated donors were immortalized and monoclonal antibodies were tested for neutralizing activity and epitope specificity. Two antibodies, identified as RVC20 and RVC58 (binding to antigenic site I and III, respectively), were selected for their potency and broad-spectrum reactivity. In vitro, RVC20 and RVC58 were able to neutralize all 35 rabies virus (RABV) and 25 non-RABV lyssaviruses. They showed higher potency and breath compared to antibodies under clinical development (namely CR57, CR4098, and RAB1) and commercially available human RIG. In vivo, the RVC20-RVC58 cocktail protected Syrian hamsters from a lethal RABV challenge and did not affect the endogenous hamster post-vaccination antibody response

Rabies Situation in Cambodia

In Cambodia, rabies still elicits fear in the communities. Since 1998 the Institut Pasteur in Cambodia (IPC), Phnom Penh has been the only source of free post-exposure prophylaxis (PEP) and post mortem diagnosis. During 1998–2007, on average ∼12,400 patients received PEP annually at IPC (range 8,907–14,475) and 63 fatal human cases presenting with encephalitis following a dog bite were reported including 73% who tested positive by fluorescent-antibody test on brain samples or/and by reverse-transcriptase polymerase chain reaction on skin, cerebrospinal fluid, or urine. In 2007, 14,475 patients received PEP (100 PEP/100,000 people in Cambodia) including 95% who resided in Phnom Penh city (615 PEP/100,000) or five neighboring provinces. Using a step-by-step probability model, we estimated that 810 human rabies deaths would occur in 2007 (95% confidence interval [CI] 394–1,607); an incidence of 5.8/100,000 (95%CI 2.8–11.5). As a result, despite high attendance at the IPC's PEP center most Cambodians living in peripheral provinces in Cambodia may not have adequate access to PEP. Finally, the model generated one of the highest incidences of rabies worldwide. A national rabies control program is needed to improve surveillance and access to PEP, and to initiate vaccination campaigns in dogs

Unifying the spatial epidemiology and molecular evolution of emerging epidemics

We introduce a conceptual bridge between the previously unlinked fields of phylogenetics and mathematical spatial ecology, which enables the spatial parameters of an emerging epidemic to be directly estimated from sampled pathogen genome sequences. By using phylogenetic history to correct for spatial autocorrelation, we illustrate how a fundamental spatial variable, the diffusion coefficient, can be estimated using robust nonparametric statistics, and how heterogeneity in dispersal can be readily quantified. We apply this framework to the spread of the West Nile virus across North America, an important recent instance of spatial invasion by an emerging infectious disease. We demonstrate that the dispersal of West Nile virus is greater and far more variable than previously measured, such that its dissemination was critically determined by rare, long-range movements that are unlikely to be discerned during field observations. Our results indicate that, by ignoring this heterogeneity, previous models of the epidemic have substantially overestimated its basic reproductive number. More generally, our approach demonstrates that easily obtainable genetic data can be used to measure the spatial dynamics of natural populations that are otherwise difficult or costly to quantify

Eliminating Rabies in Estonia

The compulsory vaccination of pets, the recommended vaccination of farm animals in grazing areas and the extermination of stray animals did not succeed in eliminating rabies in Estonia because the virus was maintained in two main wildlife reservoirs, foxes and raccoon dogs. These two species became a priority target therefore in order to control rabies. Supported by the European Community, successive oral vaccination (OV) campaigns were conducted twice a year using Rabigen® SAG2 baits, beginning in autumn 2005 in North Estonia. They were then extended to the whole territory from spring 2006. Following the vaccination campaigns, the incidence of rabies cases dramatically decreased, with 266 cases in 2005, 114 in 2006, four in 2007 and three in 2008. Since March 2008, no rabies cases have been detected in Estonia other than three cases reported in summer 2009 and one case in January 2011, all in areas close to the South-Eastern border with Russia. The bait uptake was satisfactory, with tetracycline positivity rates ranging from 85% to 93% in foxes and from 82% to 88% in raccoon dogs. Immunisation rates evaluated by ELISA ranged from 34% to 55% in foxes and from 38% to 55% in raccoon dogs. The rabies situation in Estonia was compared to that of the other two Baltic States, Latvia and Lithuania. Despite regular OV campaigns conducted throughout their territory since 2006, and an improvement in the epidemiological situation, rabies has still not been eradicated in these countries. An analysis of the number of baits distributed and the funding allocated by the European Commission showed that the strategy for rabies control is more cost-effective in Estonia than in Latvia and Lithuania