Rabies re-examined

Rabies is an acute, progressive, incurable viral encephalitis. The causative agents are neurotropic RNA viruses in the family Rhabdoviridae, genus Lyssavirus. Mammalian reservoirs include the Carnivora and Chiroptera, but rabid dogs still pose the greatest hazard worldwide. Viral transmission occurs mainly via animal bite, and once the virus is deposited in peripheral wounds, centripetal passage occurs towards the central nervous system. After viral replication, there is centrifugal spread to major exit portals, the salivary glands. The epidemiological significance of any host "carrier" state remains highly speculative. Although incubation periods average 1-3 months, disease occurrence days or years after exposure has been documented. Rabies should be suspected in patients with a concomitant history of animal bite and traditional clinical presentation, but a lack of such clues makes antemortem diagnosis a challenge. Pathogenetic mechanisms remain poorly understood, and current care entails palliative measures only. Current medical emphasis relies heavily on prevention of exposure and intervention before clinical onset. Prophylaxis encompasses thorough wound treatment, vaccine administration, and inoculation of rabies immunoglobulin. Although it is a major zoonosis, canine rabies can be eliminated, and application of new vaccine technologies permits significant disease control among wildlife species. Nevertheless, despite much technical progress in the past century, rabies is a disease of neglect and presents a modern public-health conundrum.     

Rabies control in Japan

In 1957 Japan succeeded in eradicating rabies, which had been endemic since the 18th century, due to the registration and confinement of family dogs, the elimination of stray dogs, and the compulsory vaccination of dogs. At present, however, vaccination coverage of family dogs is far lower than the required level of 70%. The facilities that are presently able to investigate rabies are limited in number. In addition, few medical institutions keep rabies vaccine in stock or offer postexposure vaccination to travelers bitten by animals in rabies endemic areas. Moreover, rabies immunoglobulin (RIG) cannot be given to such individuals because RIG is not produced at present in Japan, nor is it authorized to be imported. To keep Japan free from any rabies deaths, an improvement in vaccination coverage among dogs and in the supply of postexposure prophylaxis is required, and the establishment of a rabies surveillance system is also considered to be essential.     

History of Rabies Incidence and Rabies Control in Serbia in Support of the Zero by 2030 Campaign to Eliminate Dog-Mediated Human Rabies

Urban (principally canine-mediated) rabies has been a public health risk for people living in Serbia for centuries. The first legal act in urban rabies prevention in Serbia was established in 1834 by introducing high taxes for pet dog owners. Five years later in 1839, the first set of literature describing rabies prevention was issued by the health department from The Serbian Ministry of Interior. An overview of cauterization of rabies wounds was presented as the principal method of rabies post exposure prophylaxis. In 1890, a human rabies vaccination was introduced in Serbia with the royal government directive which ordered patients to be treated at the Pasteur Institute in Budapest in receipt of rabies vaccination. Urban (canine) rabies was eliminated during the 1980s, but sylvatic (principally fox-mediated) rabies still prevailed. The last human rabies case was recorded in the Province of Kosovo and Metohija in 1980. Sylvatic rabies in Serbia is in the final stages of elimination by orally vaccinating foxes (Vulpes vulpes). The only published finding of a lyssavirus among Serbian bats was made in 1954 by Dr Milan Nikolić in the vicinity of Novi Sad. In 2006, a comprehensive two-year active surveillance program of lyssaviruses in bats in Serbia was undertaken. In this single study, all of the bats from Serbia tested negative for a lyssavirus.     

Portable Rabies Virus Sequencing in Canine Rabies Endemic Countries Using the Oxford Nanopore MinION

As countries with endemic canine rabies progress towards elimination by 2030, it will become necessary to employ techniques to help plan, monitor, and confirm canine rabies elimination. Sequencing can provide critical information to inform control and vaccination strategies by identifying genetically distinct virus variants that may have different host reservoir species or geographic distributions. However, many rabies testing laboratories lack the resources or expertise for sequencing, especially in remote or rural areas where human rabies deaths are highest. We developed a low-cost, high throughput rabies virus sequencing method using the Oxford Nanopore MinION portable sequencer. A total of 259 sequences were generated from diverse rabies virus isolates in public health laboratories lacking rabies virus sequencing capacity in Guatemala, India, Kenya, and Vietnam. Phylogenetic analysis provided valuable insight into rabies virus diversity and distribution in these countries and identified a new rabies virus lineage in Kenya, the first published canine rabies virus sequence from Guatemala, evidence of rabies spread across an international border in Vietnam, and importation of a rabid dog into a state working to become rabies-free in India. Taken together, our evaluation highlights the MinION’s potential for low-cost, high volume sequencing of pathogens in locations with limited resources.     

Chimeric Rabies Virus-Like Particles Containing Membrane-Anchored GM-CSF Enhances the Immune Response against Rabies Virus

Rabies remains an important public health threat in most developing countries. To develop a more effective and safe vaccine against rabies, we have constructed a chimeric rabies virus-like particle (VLP), which containing glycoprotein (G) and matrix protein (M) of rabies virus (RABV) Evelyn-Rokitnicki-Abelseth (ERA) strain, and membrane-anchored granulocyte-macrophage colony-stimulating factor (GM-CSF), and it was named of EVLP-G. The immunogenicity and protective efficacy of EVLP-G against RABV were evaluated by intramuscular administration in a mouse model. The EVLP-G was successfully produced in insect cells by coinfection with three recombinant baculoviruses expressing G, M, and GM-CSF, respectively. The membrane-anchored GM-CSF possesses a strong adjuvant activity. More B cells and dendritic cells (DCs) were recruited and/or activated in inguinal lymph nodes in mice immunized with EVLP-G. EVLP-G was found to induce a significantly increased RABV-specific virus-neutralizing antibody and elicit a larger and broader antibody subclass responses compared with the standard rabies VLP (sRVLP, consisting of G and M). The EVLP-G also elicited significantly more IFN-γ- or IL-4-secreting CD4⁺ and CD8⁺ T cells than the sRVLP. Moreover, the immune responses induced by EVLP-G protect all vaccinated mice from lethal challenge with RABV. These results suggest that EVLP-G has the potential to be developed as a novel vaccine candidate for the prevention and control of animal rabies.     

Rabies in Thailand: 1990

Of the more than 100,000 courses of postexposure rabies treatment given in Thailand annually, 95% consist of brain tissue-derived vaccine without immune globulin. Rabies tissue culture vaccines and immune globulins are expensive by the standards of developing countries. When they are given according to either of two proven intradermal postexposure schedules, significant savings can be achieved without loss of efficacy. Purified equine rabies immune globulins account for approximately 10% of the cost of human products administered to exposed individuals and have been shown to be safe and effective. A canine preexposure immunogenicity study with a potent, inactivated tissue culture vaccine revealed that 12.5% of Thai dogs failed to develop protective antibody titers 2 months after one subcutaneous injection. Previous studies have shown significant antigenic differences between Thai street rabies virus and European and North African strains.