Genetic Diversity, Evolutionary Dynamics, and Pathogenicity of Ferret Badger Rabies Virus Variants in Mainland China, 2008-2018

Abstract

In contrast to dog-associated human rabies cases decline year by year due to the rabies vaccination coverage rates increase in China, ferret badger (FB, Melogale moschata)-associated human rabies cases emerged in the 1990s, and are now an increasingly recognized problem in southeast China. To investigate epidemiology, temporal evolution dynamics, transmission characterization, and pathogenicity of FB-associated rabies viruses (RABVs), from 2008 to 2018, we collected 3,622 FB brain samples in Jiangxi and Zhejiang Province, and detected 112 RABV isolates. Four FB-related lineages were identified by phylogenetic analysis (lineages A-D), the estimated Times to Most Recent Common Ancestor were 1941, 1990, 1937, and 1997 for lineages A-D, respectively. Furthermore, although no FB-associated human rabies case has been reported there apart from Wuyuan area, FB-RABV isolates are mainly distributed in Jiangxi Province. Pathogenicity of FB-RABVs was assessed using peripheral inoculation in mice and in beagles with masseter muscles, mortality-rates ranging from 20 to 100% in mice and 0 to 20% in beagles in the groups infected with the various isolates. Screening of sera from humans with FB bites and no post-exposure prophylaxis to rabies revealed that five of nine were positive for neutralizing antibodies of RABV. All the results above indicated that FB-RABV variants caused a lesser pathogenicity in mice, beagles, and even humans. Vaccination in mice suggests that inactivated vaccine or recombinant subunit vaccine products can be used to control FB-associated rabies, however, oral vaccines for stray dogs and wildlife need to be developed and licensed in China urgently.

Keywords: epidemiology and evolution; ferret badger; neutralizing antibody; pathogenicity; rabies virus.

FIGURE 1

Continental distribution of ferret badger (FB) rabies virus (RABV) isolates in southeast China during 2008–2018. The 41 FB RABV isolates in Lineage A were mainly distributed in Qiandao lake (Zhejiang province) and east Poyang lake (Jiangxi province) regions. Lineage B had 17 isolates from Fuzhou district, south of Poyang lake. Lineage C included 47 isolates, 41 distributed in west Poyang lake, and the other 6 in east Poyang lake, mixing geographically with Lineage A. Lineage D had 4 isolates in Taizhou district, Zhejiang province and 3 in east Poyang lake.

FIGURE 2

Maximum likelihood phylogeny of 244 RABV sequences separates the 112 FB-associated RABVs into 4 distinct Lineages: A, B, C, and D. Lineage A was rooted with China dog RABV Group II, Lineages B and D with China dog RABV Group I, and Lineage C was independent, sitting in the middle of Group I and II. The numbers below the branches were bootstrap values (%) of 1,000 replicates.

FIGURE 3

Rabies virus neutralizing antibody (RVNA) titers after 14 days vaccination in mice.