Author(s): Ming Zhou 1,2,3, Guoqing Zhang 2, Guiping Ren 2, Clement W. Gnanadurai 2, Zhenguang Li 2, Qingqing Chai 2, Yang Yang 2, Christina M. Leyson 2, Wenxue Wu 3, Min Cui 1, Zhen F. Fu 1,2,*
Rabies remains a public health threat around the globe and more than 55,000 humans die each year from rabies , . Most of the human cases occur in the developing countries of Asia and Africa where canine rabies is endemic . Routine vaccination of dogs is not carried out due to the lack of political will, limited resources and the large population of stray dogs, which are not accessible for parenteral vaccination, resulting in the low coverage of vaccination in dogs .In the developed countries, human rabies has been eliminated or reduced to a minimum due to rabies control programs during the past 60 years (routine and mass vaccination of dogs) . However, rabies in wildlife becomes a major threat. It has been reported that more than 90% animal rabies cases occur in wildlife such as raccoons, bats, skunks and foxes in the United States , . Bat rabies, particularly the silver-haired bat rabies virus (SHBRV), emerged to be the major source for human infections in the past two decades , .Therefore, major challenges for rabies control are to immunize stray dogs in the developing countries and wildlife in the developed countries.
Currently inactivated vaccines are used for routine vaccination of pet animals , however, multiple immunizations have to be carried out to provide sufficient immunity throughout the life of the animals. Furthermore, vaccination of puppies <3 months of age fails to induce protective immunity, although maternal antibodies declined to undetectable levels by 6 weeks of age . There is a period from the time of the waning maternal antibody to the time of active immunity during which the young animals may not be protected . Most importantly, the inactivated vaccines are expensive to be used in the developing countries and the population of stray dogs is not accessible for any vaccines given parenterally . It is thus important to develop ways for immunizing stray dogs.
Oral rabies vaccines have been successfully developed for wildlife. In the earlier days, an attenuated RABV, Street Alabama Dufferin (SAD) B19, was used in Europe, which resulted in immunization of foxes and stopped RABV spread to untreated areas , . However, SAD can cause disease in rodents  and domestic animals . Further attenuation of SAD by selecting neutralizing antibody escape mutants resulted in the development of SAG-2 ,  that has been used as vaccine for wildlife in many countries in Europe -. However, a low level of virus-neutralizing antibody (VNA) response has been reported after oral immunization in dogs with SAG-2 . Another widely used oral vaccine for wildlife is the recombinant vaccinia virus expressing RABV G (VRG) . Application of VRG in bait systems resulted in large-scale elimination of fox rabies in parts of Europe . Similar applications of VRG in the United...