Zoonotic spillover, which is the transmission of a pathogen from a vertebrate animal to a human, presents a global public health burden but is a poorly understood phenomenon. Zoonotic spillover requires several factors to align, including the ecological, epidemiological and behavioural determinants of pathogen exposure, and the within-human factors that affect susceptibility to infection. In this Opinion article, we propose a synthetic framework for animal-to-human transmission that integrates the relevant mechanisms. This framework reveals that all zoonotic pathogens must overcome a hierarchical series of barriers to cause spillover infections in humans. Understanding how these barriers are functionally and quantitatively linked, and how they interact in space and time, will substantially improve our ability to predict or prevent spillover events. This work provides a foundation for transdisciplinary investigation of spillover and synthetic theory on zoonotic transmission.

/pdf/pathways-to-zoonotic-spillover-5230h7thxs.pdf

Pathways to zoonotic spillover

Vaccinia virus, no longer required for immunization against smallpox, now serves as a unique vector for expressing genes within the cytoplasm of mammalian cells. As a research tool, recombinant vaccinia viruses are used to synthesize and analyze the structure-function relationships of proteins, determine the targets of humoral and cell-mediated immunity, and investigate the types of immune response needed for protection against specific infectious diseases and cancer. The vaccine potential of recombinant vaccinia virus has been realized in the form of an effective oral wild-life rabies vaccine, although no product for humans has been licensed. A genetically altered vaccinia virus that is unable to replicate in mammalian cells and produces diminished cytopathic effects retains the capacity for high-level gene expression and immunogenicity while promising exceptional safety for laboratory workers and potential vaccine recipients.

https://www.pnas.org/content/pnas/93/21/11341.full.pdf

Genetically engineered poxviruses for recombinant gene expression, vaccination, and safety

The major goals of veterinary vaccines are to improve the health and welfare of companion animals, increase production of livestock in a cost-effective manner, and prevent animal-to-human transmission from both domestic animals and wildlife. These diverse aims have led to different approaches to the development of veterinary vaccines from crude but effective whole-pathogen preparations to molecularly defined subunit vaccines, genetically engineered organisms or chimeras, vectored antigen formulations, and naked DNA injections. The final successful outcome of vaccine research and development is the generation of a product that will be available in the marketplace or that will be used in the field to achieve desired outcomes. As detailed in this review, successful veterinary vaccines have been produced against viral, bacterial, protozoal, and multicellular pathogens, which in many ways have led the field in the application and adaptation of novel technologies. These veterinary vaccines have had, and continue to have, a major impact not only on animal health and production but also on human health through increasing safe food supplies and preventing animal-to-human transmission of infectious diseases. The continued interaction between animals and human researchers and health professionals will be of major importance for adapting new technologies, providing animal models of disease, and confronting new and emerging infectious diseases.

Current Status of Veterinary Vaccines

/pdf/managing-vertebrate-pests-foxes-qcmqks0uui.pdf

Managing vertebrate pests: foxes.

Many pathogens, such as the agents of West Nile encephalitis and plague, are maintained in nature by animal reservoirs and transmitted to humans by arthropod vectors. Efforts to reduce disease incidence usually rely on vector control or immunization of humans. Lyme disease, for which no human vaccine is currently available, is a commonly reported vector-borne disease in North America and Europe. In a recently developed, ecological approach to disease prevention, we intervened in the natural cycle of the Lyme disease agent (Borrelia burgdorferi) by immunizing wild white-footed mice (Peromyscus leucopus), a reservoir host species, with either a recombinant antigen of the pathogen, outer surface protein A, or a negative control antigen in a repeated field experiment with paired experimental and control grids stratified by site. Outer surface protein A vaccination significantly reduced the prevalence of B. burgdorferi in nymphal blacklegged ticks (Ixodes scapularis) collected at the sites the following year in both experiments. The magnitude of the vaccine's effect at a given site correlated with the tick infection prevalence found on the control grid, which in turn correlated with mouse density. These data, as well as differences in the population structures of B. burgdorferi in sympatric ticks and mice, indicated that nonmouse hosts contributed more to infecting ticks than previously expected. Thus, where nonmouse hosts play a large role in infection dynamics, vaccination should be directed at additional species.

An ecological approach to preventing human infection: Vaccinating wild mouse reservoirs intervenes in the Lyme disease cycle

Rabies infection of domestic and wild animals is a serious problem throughout the world. The major disease vector in Europe is the red fox (Vulpes vulpes) and rabies control has focused on vaccinating and/or culling foxes. Culling has not been effective, and the distribution of five vaccine baits is the only appropriate method for the vaccination of wild foxes. Although some European countries have conducted field vaccination campaigns using attenuated rabies virus strains, their use has not been extensively approved because they retain pathogenicity for rodents and can revert to virulence. These strains cannot be used in North America because they are pathogenic for the striped skunk (Mephitis mephitis) and are ineffective in the raccoon (Procyon lotor). We have constructed a recombinant vaccinia virus, VVTGgRAB, expressing the surface glycoprotein (G) of rabies virus (ERA strain). The recombinant was a highly effective vaccine in experimental animals, in captive foxes and in raccoons. We report here the results of a large-scale campaign of fox vaccination in a 2,200 km2 region of southern Belgium, an area in which rabies is prevalent. After distribution, 81% of foxes inspected were positive for tetracycline, a biomarker included in the vaccine bait and, other than one rabid fox detected close to the periphery of the treated area, no case of rabies, either in foxes or in domestic livestock, has been reported in the area.

/pdf/large-scale-eradication-of-rabies-using-recombinant-vaccinia-1enc1xngol.pdf

Large-scale eradication of rabies using recombinant vaccinia-rabies vaccine

A field trial of fox vaccination against rabies using a vaccinia-rabies recombinant virus was carried out in Belgium on October 24, 1987. Each vaccine capsule contained a suspension of 10(8) TCID50 of the recombinant virus and was introduced into a chicken head. Each chicken head contained 150 mg of tetracycline as a marker of uptake. Two hundred and fifty heads were distributed in an area of 6 km2 situated within a military zone. The bait uptake was monitored for 15 days after the distribution. Sixty-three per cent of the chicken heads were taken by wild animals within that period. The trial was controlled according to the rules defined by the World Health Organisation.

/pdf/first-field-trial-of-fox-vaccination-against-rabies-using-a-34cnr5er2w.pdf

First field trial of fox vaccination against rabies using a vaccinia-rabies recombinant virus.

Use of a vaccinia-rabies recombinant virus for the oral vaccination of foxes against rabies

De 1989 a 1991, l'ensemble du territoire infecte (10000 km2) fut traite a cinq reprises. Lors des deux premieres campagnes de vaccination, deux types de vaccins ont ete utilises : la souche attenuee du virus rabique SAD B19 et le virus recombinant vaccine-rage (V-RG). A partir de l'automne 1990, le V-RG a ete utilise exclusivement. Ces cinq operations ont provoque une importante diminution de l'incidence de la rage et ont permis l'elimination de la maladie dans 80% du territoire initialement infecte. En 1992, un foyer transfrontalier persistait dans le sud du pays. C'est pourquoi, de 1992 a 1994, des campagnes ont ete realisees sur un territoire plus restreint, le long des frontieres politiques. En 1993, l'absence de cas vulpin de rage laissait suggerer que l'ensemble du territoire infecte avait ete rendu indemne. Toutefois, en 1994, la detection d'un renard enrage revelait la presence d'un foyer residuel a proximite de la frontiere francaise. Malgre la realisation de nouvelles campagnes de vaccination dans cette region, ce foyer a pu se propager vers le nord et reinfecter, en 1995, un territoire d'environ 3000 km2. C'est pourquoi, a partir de 1996, la strategie de vaccination a ete modifiee et adaptee a cette situation epidemiologique nouvelle qu'etait la reinfection d'un territoire prealablement rendu indemne et ce, en presence d'une densite accrue de la population vulpine. Grâce a cette nouvelle strategie de vaccination ainsi qu'a une meilleure cooperation internationale, le foyer de reinfection a pu etre maitrise. Les deux derniers cas rapportes en Belgique furent un renard et une bete bovine detectes respectivement le 3 avril 1998 et le 17 juillet 1999 dans la commune de Bastogne, limitrophe du Grand-Duche de Luxembourg. En accord avec les recommandations de l'Organisation Mondiale de la Sante et les directives de l'Office International des Epizooties, la Belgique, conjointement avec le Grand-Duche de Luxembourg, a introduit une demande pour etre declaree officiellement indemne de rage des juillet 2001.

/pdf/elimination-de-la-rage-en-belgique-par-la-vaccination-du-1voeaahk6d.pdf

B. Bauduin

Papers

Large-scale eradication of rabies using recombinant vaccinia-rabies vaccine

First field trial of fox vaccination against rabies using a vaccinia-rabies recombinant virus.

Use of a vaccinia-rabies recombinant virus for the oral vaccination of foxes against rabies

Elimination de la rage en Belgique par la vaccination du renard roux (Vulpes vulpes)

Enquête sur l'infestation du renard roux (Vulpes vulpes) par Echinococcus multilocularis en province de Luxembourg (Belgique)