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Factors affecting transmission and protective immunity of European Bat Lyssaviruses - SE0421

Description
The UK is free of terrestrial rabies, however, five cases of European Bat Lyssavirus type 2 (EBLV-2) have occurred (1996 – 2004); four in Daubenton’s bats, and one human case in a bat conservationist. The route and source of exposure and the number of positive exposures resulting in infection in these cases are not known. In Europe there have been 14 additional cases including one human, again a bat handler. EBLV-1 has not been recorded in the UK, however, its prevalence is high in Europe; ~790 cases mainly in Serotine bats, five sheep, one stone marten and two human cases. Antibodies to both EBLVs have been detected in bats in the UK, indicating that ‘healthy’ bats have been previously exposed to these viruses. Antibodies to EBLV-1 have also been detected in a cat from Denmark. Raised antibodies are also observed in experimentally infected animals (foxes and sheep) that have survived intra-muscular exposure to both EBLV-1 and EBLV-2.

Rabies viruses have possibly co-evolved with bat hosts and then infections became established in other terrestrial mammal groups. As a result these viruses may be ‘tolerated’ in bat populations, in that they survive exposure under normal circumstances via natural immunity, but not in all situations. However, this process may also provide an evolutionary route where viruses are selected under ‘immune pressure’ and those that are not eliminated represent ‘survival of the fittest’ and are more capable of host adaptation and subsequent ‘spill-over’ into other mammal species.

Factors affecting the development of disease may be related to immuno-suppression; hibernation, pregnancy, physiological, nutritional or other stress initiators. Antibody mediated enhancement of virus replication following multiple exposure; bats grooming behaviours and bat handler activities, may also result in activation of disease. Multiple exposures have been implicated in the two human cases of EBLV-2. Although controversial, we cannot exclude the possibility that sub-clinical infections and viral persistence at the site of infection may also play a role in long incubation periods / ‘asymptomatic carrier’ status, as reported for a variety lyssaviurses. Combined or in combined these factors may contribute to activation of delayed disease if the virus has not been eliminated via ‘sterilising’ immunity.

In order to assess the hazard and risk of bat rabies disease transmission in the UK a better understanding of the EBLV virus-host relationship and the factors affecting host immunity will be required.

Benefits, Aims & Objectives:
The principal benefit will be in informing policy (Defra and DoH) on the hazards and risks involved in potential transmission of EBLV ‘bat rabies’ from bats to other mammal hosts and under what circumstances this may occur. Natural and experimental infections indicate that EBLVs can cause disease in wildlife, livestock and man. Transmission however may be restricted depending on the route of infection, the dose of virus, the number of exposures and the type of immune response that occurs in the host. In addition, commercially available rabies vaccines provide protection against EBLVs and three of the four Eurasian isolates but not West Caucasian Bat Virus. However, the minimum level of virus neutralising antibody required to prevent disease with EBLVs is yet to be determined, an area of study recommended recently by the OIE- World Organisation for Animal Health - rabies review committee., 2005.

At the VLA we have developed assays to study the immune response (antibody) to lyssavirus vaccination and infection, the route of infection (hand/foot, muscle or central nervous system), the role of peripheral virus replication (muscle) in development of disease and models to examine the level of protection against EBLVs provided by current rabies vaccines (murine vaccination/challenge models) [SE0413/418]. In addition, we are using experimental models to investigate the role of the innate and adaptive immune response in potential hosts [SE0521/524].

The proposed studies would expand on this programme of work and inform policy on animal health and welfare, rabies free status, quarantine periods for imported animals and international trade issues involving rabies, including 'bat rabies'. Our aims are to study bat rabies transmission, susceptibility and protection of animal health (and by implication human), improve virus (EBLVs and clasical rabies) diagnosis and detection from saliva and other body fluids (such as urine, faeces, sputum, blood etc) which have an impact on disease surveillance and rabies status in the UK, and an understanding of long incubation periods and/or 'carrier' status of rabies which have direct relevance to quarantine and international trade. These studies will also provide data for recommendations on human health issues.

The main objectives are listed below:
- Correlate the minimum measurable rabies vaccine induced virus neutralisation antibody titre of 0.5 IU/ml with protective immunity to EBLVs.
- Determination of the impact of multiple exposure to EBLVs and possible reactivation of virus.
- Establish the level of Lyssavirus excretion during the non-clinical and early clinical phases of disease.
- To elucidate the mechanisms involved in the immune response during survival or susceptibility to disease following peripheral exposure.
Objective
1. Correlate the minimum measurable rabies vaccine induced virus neutralisation antibody titre of 0.5 IU/ml with protective immunity to EBLVs.

2. Determination of the impact of multiple exposure to EBLVs and possible re-activation of virus.

3. Establish the level of Lyssavirus excretion during the non-clinical and early clinical phases of disease.

4. To elucidate the mechanisms involved in survival or susceptibility to disease following peripheral exposure.
Project Documents
• EVID4 - Final project report : Final report for the project SE0421   (344k)
• ANX - Annex : SE0421 SID5 Final report _Annex   (1148k)
Time-Scale and Cost
From: 2006

To: 2011

Cost: £784,396
Contractor / Funded Organisations
Veterinary Laboratories Agency
Keywords
Animal Health              
Bats              
Immunity              
Plants and Animals              
Rabies              
Transmission              
Zoonoses              
Fields of Study
Animal Health