MicrobiologyBytes

Researchers have developed a single vaccine which protects against both rabies and Ebola virus. These two viruses are related to each other, but do not cross-react serologically. By inserting elements of the Ebola virus GP protein into an existing rabies virus vaccine, a single bivalent vaccine was produced. Although it works in the laboratory, the new vaccine – or something similar based on this first attempt – need to be tested in primates and eventually in humans.

Apart from people, Ebola virus is thought to have eradicated thousands of gorillas, prompting the World Conservation Union to raise their status to “critically endangered” in 2007, the first time a mammal has become critically endangered as a direct result of disease. Vaccination could help prevent future deaths.

Inactivated or Live-Attenuated Bivalent Vaccines that Confer Protection against Rabies and Ebola Viruses. J Virol. Aug 17 2011
The search for a safe and efficacious vaccine for Ebola virus continues as no current vaccine candidate is nearing licensure. We have developed (a) replication-competent, (b) replication-deficient, and (c) chemically inactivated rabies virus (RABV) vaccines expressing Zaire ebolavirus (ZEBOV) glycoprotein (GP) using a reverse genetics system based on the SAD B19 RABV wildlife vaccine. ZEBOV GP is efficiently expressed by these vaccine candidates and is incorporated into virions. The vaccine candidates were avirulent after inoculation of adult mice, and viruses with a deletion in the RABV glycoprotein have greatly reduced neurovirulence after intracerebral inoculation in suckling mice. Immunization with live or inactivated RABV vaccines expressing ZEBOV GP induced humoral immunity against each virus and conferred protection from both lethal RABV and EBOV challenge in mice. The bivalent RABV/ZEBOV vaccines described here have several distinct advantages that may speed the development of inactivated vaccines for use in humans and potentially live or inactivated vaccines for endemic nonhuman primates at risk of EBOV infection.

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At least 15 million doses of anti-rabies post-exposure prophylaxis are administered annually worldwide, and an estimated 55,000 people die of rabies every year. Over 99% of these deaths occur in developing countries, predominantly in Asia and in Africa where rabies is endemic in domestic dogs. Despite the global health burden due to rabies, little is known about the patterns of the spread of dog rabies in these endemic regions. A recent paper examines the dynamics and determinants of the spatial diffusion of dog rabies viruses in North Africa based on virus genetic data. This analysis reveals a combination of restricted spread across administrative borders, the occasional long-distance movement of rabies viruses, and a strong fit between spatial spread of the virus and road distances between localities. Together, these data indicate that by transporting dogs, humans have played a key role in the dispersal of a major animal pathogen. This study provides essential new information on the transmission dynamics of rabies in Africa and will greatly assist in future intervention strategies.

Phylodynamics and Human-Mediated Dispersal of a Zoonotic Virus. (2010) PLoS Pathog 6(10): e1001166. doi:10.1371/journal.ppat.1001166
Understanding the role of humans in the dispersal of predominately animal pathogens is essential for their control. We used newly developed Bayesian phylogeographic methods to unravel the dynamics and determinants of the spread of dog rabies virus (RABV) in North Africa. Each of the countries studied exhibited largely disconnected spatial dynamics with major geo-political boundaries acting as barriers to gene flow. Road distances proved to be better predictors of the movement of dog RABV than accessibility or raw geographical distance, with occasional long distance and rapid spread within each of these countries. Using simulations that bridge phylodynamics and spatial epidemiology, we demonstrate that the contemporary viral distribution extends beyond that expected for RABV transmission in African dog populations. These results are strongly supportive of human-mediated dispersal, and demonstrate how an integrated phylogeographic approach will turn viral genetic data into a powerful asset for characterizing, predicting, and potentially controlling the spatial spread of pathogens.

Related:

• Transmission and elimination of rabies
• Pre-exposure and Post-exposure Prevention of rabies
• World Rabies Day, 28 September

According to official estimates, rabies kills 55,000 people each year, primarily in India, Southeast Asia and Africa. However, the death toll is probably much higher; one report estimates that the number of deaths in some areas is possibly 100 times that reported. As rabies cases do not need to be reported to the authorities in many countries, and many people do not seek treatment or are misdiagnosed, obtaining an accurate estimate of the overall prevalence is difficult. Even the official death toll is higher than that for diseases such as human African trypanosomiasis, leishmaniasis and Chagas disease.

As with other diseases that are preventable and treatable, such as pneumonia, it seems unthinkable that rabies still claims so many lives. Successful control of rabies in the United Kingdom and the Americas shows that rabies can be controlled and possibly eliminated. Further research will bring us closer to this goal, but it will require funding agencies and governments to better understand the scope of the problem. Until then, important events like World Rabies Day will remain vital to shed light on this neglected problem.

Biting back against rabies. Nature Reviews Microbiology 8: 676 (October 2010) doi:10.1038/nrmicro2451

Related:

• Transmission and elimination of rabies
• Simplified rabies vaccination
• Pre-exposure and Post-exposure Prevention of rabies

Rabies causes an estimated 55,000 human deaths globally each year, 23,750 of which occur in Africa. Moreover, 11 million people undergo rabies postexposure prophylaxis (PEP) worldwide each year. Rabies is a zoonotic disease with dogs remaining the principal host in Asia, parts of America, and large parts of Africa, and rabid dogs are the cause of most human rabies cases. Between 30% to 60% of the victims of dog bites are children under the age of 15. Inappropriate dog vaccination programs, limited access to vaccination, and postexposure treatment of individuals that have been exposed to rabid dogs are major problems in developing countries.

Rabies virus (RV), a negative-stranded RNA virus of the rhabdoviridae family, has a relatively simple, modular genome that encodes 5 structural proteins: a RNA-dependent RNA polymerase (L), a nucleoprotein (N), a phosphorylated protein (P), a matrix protein (M), and an external surface glycoprotein (G). The N, P, and L together with the genomic RNA form the ribonucleoprotein complex (RNP). The main feature of rabies virus is neuroinvasiveness, which refers to its unique ability to invade the CNS from peripheral sites. Virus uptake, axonal transport, trans-synaptic spread, and the rate of virus replication are key factors that determine the neuroinvasiveness of RV.

The regulation of virus replication also appears to be one of the important mechanisms contributing to RV pathogenesis. Pathogenic RV strains replicate at a lower rate than attenuated strains, which helps preserve the structure of neurons that is used by the viruses to reach the CNS. In addition, the lower expression levels of virus antigens, in particular the RV G, which is the major viral antigen responsible for the induction of protective immunity, hinders early detection by the host immune system. In contrast to wildlife RVs, most attenuated RV strains replicate very quickly and express large amounts of G, thereby inducing strong adaptive immune responses that result in virus clearance. These properties provide the basis for the use of attenuated RV strains for the pre- and PEP of rabies. A live-attenuated RV vaccine is likely to provide effective immunization with a single dose, which has practical, cost, and logistical advantages over conventional multi-dose vaccines with respect to the worldwide eradication of dog rabies. In addition, because live-attenuated RV vaccines are capable of inducing immune responses that can clear virulent RVs from the CNS, there is the possibility that such vaccines could serve as the foundation for the treatment of early stage human rabies.

Effective preexposure and postexposure prophylaxis of rabies with a highly attenuated recombinant rabies virus. PNAS USA 2009 106(27): 11300-5
Rabies remains an important public health problem with more than 95% of all human rabies cases caused by exposure to rabid dogs in areas where effective, inexpensive vaccines are unavailable. Because of their ability to induce strong innate and adaptive immune responses capable of clearing the infection from the CNS after a single immunization, live-attenuated rabies virus (RV) vaccines could be particularly useful not only for the global eradication of canine rabies but also for late-stage rabies postexposure prophylaxis of humans. To overcome concerns regarding the safety of live-attenuated RV vaccines, we developed the highly attenuated triple RV G variant, SPBAANGAS-GAS-GAS. In contrast to most attenuated recombinant RVs generated thus far, SPBAANGAS-GAS-GAS is completely nonpathogenic after intracranial infection of mice that are either developmentally immunocompromised (e.g., 5-day-old mice) or have inherited deficits in immune function (e.g., antibody production or type I IFN signaling), as well as normal adult animals. In addition, SPBAANGAS-GAS-GAS induces immune mechanisms capable of containing a CNS infection with pathogenic RV, thereby preventing lethal rabies encephalopathy. The lack of pathogenicity together with excellent immunogenicity and the capacity to deliver immune effectors to CNS tissues makes SPBAANGAS-GAS-GAS a promising vaccine candidate for both the preexposure and postexposure prophylaxis of rabies.

Related:

• Transmission and elimination of rabies
• Simplified rabies vaccination
• Negative sense RNA viruses

Rabies has been one of the most feared diseases throughout human history and has the highest human case-fatality proportion of any infectious disease. Every year over 7 million people receive post-exposure prophylaxis, and an estimated 55,000 people die from rabies. Over 99% of these deaths occur in developing countries where rabies is endemic in domestic dog populations. However, the impacts of canine rabies are often overlooked, largely because human rabies deaths are now extremely rare in Western Europe and North America, where mass vaccination successfully eliminated the disease from domestic dog populations.

Although canine rabies has been successfully eliminated from Western Europe and North America, in the developing world someone dies every ten minutes from this horrific disease, which is primarily spread by domestic dogs. A quantitative understanding of rabies transmission dynamics in domestic dog populations is crucial to determining whether global elimination can be achieved. The unique pathology of rabies allowed researchers to trace case-to-case transmission directly during a rabies outbreak in northern Tanzania. From these unusual data, they generated a detailed analysis of rabies transmission biology and found evidence for surprisingly low levels of transmission. They also analysed outbreak data from around the world and found that the transmission of canine rabies has been inherently low throughout its global historic range, explaining the success of control efforts in developed countries. However, they show that when birth and death rates in domestic dog populations are high, such as in the study populations in Tanzania, it is more difficult to maintain population-level immunity in between vaccination campaigns. Nonetheless, although the level of vaccination coverage required is higher than would be predicted from naïve transmission models, global elimination of canine rabies can be achieved through appropriately designed, sustained domestic dog vaccination campaigns.

Transmission dynamics and prospects for the elimination of canine rabies. PLoS Biol. 2009 Mar 10;7(3):e53
Rabies has been eliminated from domestic dog populations in Western Europe and North America, but continues to kill many thousands of people throughout Africa and Asia every year. A quantitative understanding of transmission dynamics in domestic dog populations provides critical information to assess whether global elimination of canine rabies is possible. We report extensive observations of individual rabid animals in Tanzania and generate a uniquely detailed analysis of transmission biology, which explains important epidemiological features, including the level of variation in epidemic trajectories. We found that the basic reproductive number for rabies, R0, is very low in our study area in rural Africa (approximately 1.2) and throughout its historic global range (<2). This finding provides strong support for the feasibility of controlling endemic canine rabies by vaccination, even near wildlife areas with large wild carnivore populations. However, we show that rapid turnover of domestic dog populations has been a major obstacle to successful control in developing countries, thus regular pulse vaccinations will be required to maintain population-level immunity between campaigns. Nonetheless our analyses suggest that with sustained, international commitment, global elimination of rabies from domestic dog populations, the most dangerous vector to humans, is a realistic goal.

Related:

• Simplified rabies vaccination
• Negative sense RNA viruses