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Page 16 Jaswant et al. One Health Implement Res 2024;4:15-37 https://dx.doi.org/10.20517/ohir.2023.61

Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted and synthesised to
provide recommendations for further research and application to support rabies control.

Results: 220 studies were identified to have documented rabies virus (RABV) sequences from 94 countries,
primarily using first-generation technology to produce partial genomes and with sequencing predominantly
conducted overseas rather than in-country. Dogs were identified to be the primary RABV reservoir in these regions,
although some studies identified more localised wildlife reservoirs. Clade classifications were commonly based on
host association or geographical location, however, lack of standardised methods and nomenclature for classifying
lineages limited comparison at higher resolution. Cross-species transmission, and both local and long-distance
transmission were identified, although quantitative inference was limited. Sequence data was particularly useful for
identifying transboundary spread and incursions, investigating host shifts, and tracing sources of human rabies,
with endemicity typically characterised by the identification of multiple co-circulating viral lineages.

Conclusion: There is an urgent need for standardised classification methods and phylogeny-based nomenclature
for RABVs, and for improved sequencing capacity in regions with endemic dog-mediated rabies, including
proficiency in bioinformatics and phylogenetics. Our findings emphasise the critical need to foster international
cooperation and coordinate rabies control efforts to reduce transboundary spread, limit reintroductions and
maintain progress towards the 2030 target.

Keywords: Rabies virus, genetic sequencing, phylogenetic analysis, rabies control and prevention, surveillance

INTRODUCTION
Rabies virus (RABV) poses a major public health threat, causing around 60,000 deaths annually, almost
exclusively in Low- and Middle-Income Countries (LMICs) . The virus is most commonly transmitted
[1]
[2]
through bites from infected hosts in the orders Chiroptera and Carnivora . Domestic dogs are the main
source of transmission to humans but, as a multi-host pathogen, wild carnivores also serve as primary
RABV hosts with host-associated variants recorded in certain geographies . For example, wildlife such as
[3]
raccoons, skunks and foxes each maintain different RABV variants in localities across North America .
[3]
Generally, RABV is referred to according to these host-associated variants (sometimes termed biotype , see
[4]
defined key terms in Table 1).

Phylogenetic analysis enables further classification of RABV diversity into clades, subclades and lineages.
The RABV genome is 12 kilobases (kb) in length , comprising five genes encoding the nucleoprotein (N),
[21]
phosphoprotein (P), matrix protein (M), glycoprotein (G) and the large polymerase protein (L) . Like
[22]
other RNA viruses, RABV exhibits elevated mutation rates because of the absence of proofreading . These
[23]
mutation rates foster genetic diversity, facilitating tracking of viral spread and enhanced understanding of
viral dynamics.

There is no treatment for rabies once clinical signs begin, but post-exposure prophylaxis (PEP) correctly
administered shortly after exposure is almost 100% effective in preventing the fatal onset of disease .
[24]
However, a highly effective canine vaccine is available to prevent disease in the primary reservoir, and
therefore prevent transmission to humans. Canine rabies elimination is possible through mass dog
[25]
vaccination, as demonstrated in Europe, North America, and parts of Asia and Latin America . Several
countries where dog-mediated rabies was endemic have now been declared rabies-free or are approaching
elimination as a result of sustained dog vaccination . According to the World Health Organisation, to
[25]
eliminate dog-mediated rabies vaccination campaigns need to achieve coverage of at least 70% and be
conducted annually for at least three years . Rabies incidence in Latin America has declined dramatically
[26]