Transatlantic spread of highly pathogenic avian influenza H5N1 by wild birds from Europe to North America in 2021.

Highly pathogenic avian influenza (HPAI) viruses of the A/Goose/Guangdong/1/1996 lineage (GsGd), which threaten the health of poultry, wildlife and humans, are spreading across Asia, Europe, Africa and North America but are currently absent from South America and Oceania. In December 2021, H5N1 HPAI viruses were detected in poultry and a free-living gull in St. John's, Newfoundland and Labrador, Canada. Our phylogenetic analysis showed that these viruses were most closely related to HPAI GsGd viruses circulating in northwestern Europe in spring 2021. Our analysis of wild bird migration suggested that these viruses may have been carried across the Atlantic via Iceland, Greenland/Arctic or pelagic routes. The here documented incursion of HPAI GsGd viruses into North America raises concern for further virus spread across the Americas by wild bird migration.

Quantifying Levels of Peste Des Petits Ruminants (PPR) Virus in Excretions from Experimentally Infected Goats and Its Importance for Nascent PPR Eradication Programme.

Following the successful eradication of rinderpest, the World Organization of Animal Health (OIE) and the Food and Agriculture Organisation (FAO) have set a goal to globally eradicate Peste des petits ruminants (PPR) by 2030. To support the eradication programme we have quantified the levels of PPR virus (PPRV) nucleic acid excreted in body fluids (blood, feces, saliva, nasal and eye swabs) of PPRV-infected goats to ascertain which days post-infection animals are potentially infectious, and hence direct quarantine activities. The data will also indicate optimal sample strategies to assess presence of PPR infection in the naturally infected herd. Peak PPRV nucleic acid detection in different bodily fluids was between 5 and 10 days post-infection. As such, this period must be considered the most infectious period for contact transmission, although high viral load was observed through RNA detection in nasal excretions from two days post-infection until at least two weeks post-infection. Percentage sample positivity was low both in eye swabs and saliva samples during the early stage of infection although RNA was detected as late as two weeks post-infection. From the individual animal data, PPRV was detected later post-infection in fecal material than in other body fluids and the detection was intermittent. The results from this study indicate that nasal swabs are the most appropriate to sample when considering molecular diagnosis of PPRV.

Antigenic site changes in the rabies virus glycoprotein dictates functionality and neutralizing capability against divergent lyssaviruses.

Lyssavirus infection has a near 100 % case fatality rate following the onset of clinical disease, and current rabies vaccines confer protection against all reported phylogroup I lyssaviruses. However, there is little or no protection against more divergent lyssaviruses and so investigation into epitopes within the glycoprotein (G) that dictate a neutralizing response against divergent lyssaviruses is warranted. Importantly, the facilities required to work with these pathogens, including wild-type and mutated forms of different lyssaviruses, are scarcely available and, as such, this type of study is inherently difficult to perform. The relevance of proposed immunogenic antigenic sites within the lyssavirus glycoprotein was assessed by swapping sites between phylogroup-I and -II glycoproteins. Demonstrable intra- but limited inter-phylogroup cross-neutralization was observed. Pseudotype viruses (PTVs) presenting a phylogroup-I glycoprotein containing phylogroup-II antigenic sites (I, II III or IV) were neutralized by antibodies raised against phylogroup-II PTV with the site II (IIb, aa 34-42 and IIa, aa 198-200)-swapped PTVs being efficiently neutralized, whilst site IV-swapped PTV was poorly neutralized. Specific antibodies raised against PTV-containing antigenic site swaps between phylogroup-I and -II glycoproteins neutralized phylogroup-I PTVs efficiently, indicating an immunodominance of antigenic site II. Live lyssaviruses containing antigenic site-swapped glycoproteins were generated and indicated that specific residues within the lyssavirus glycoprotein dictate functionality and enable differential neutralizing antibody responses to lyssaviruses.

Rabies pathogenesis and immunology.

Once clinical disease is manifest, the rabies virus is one of the few pathogens known to science with a near 100% fatality rate and, as such, this zoonotic pathogen has shaped both humanity and the history of science. However, today rabies is still considered to be a neglected tropical disease, despite the fact that it causes more than 59,000 human deaths each year. Although effective vaccines are available to combat the disease, the underlying mechanisms of its pathogenicity and immunology remain poorly defined. In this paper, the existing knowledge of the pathogenesis and immunological response to the rabies virus in infected hosts is described.

Le virus rabique est l'un des rares agents pathogènes connus capables de conduire à une mort quasi certaine lorsque la phase clinique de la maladie est atteinte. En tant que telle, cette zoonose a toujours marqué tant les sociétés humaines que l'histoire de la science. Pourtant, la rage est toujours considérée aujourd'hui comme une maladie tropicale négligée bien qu'elle continue de faire plus de 59 000 victimes humaines chaque année. Si des vaccins efficaces sont disponibles pour prévenir l'infection rabique, les mécanismes sous-jacents de la pathogenèse de la rage ou la réponse immunitaire qu'elle provoque chez l'hôte infecté demeurent peu connus. Les auteurs font le point sur l'état actuel des connaissances dans ce domaine.

Una vez se ha manifestado la enfermedad en su forma clínica, el virus de la rabia es uno de los pocos patógenos conocidos por los científicos que presenta una tasa de letalidad cercana al 100%. De ahí que este patógeno zoonótico haya dejado su impronta tanto en la humanidad como en la historia de la ciencia. Todavía hoy, sin embargo, pese a que causa la muerte de más de 59 000 personas al año, la rabia sigue siendo considerada una enfermedad tropical desatendida. Si bien hay vacunas eficaces para combatir la enfermedad, aún no se conocen bien los mecanismos que subyacen a su patogenicidad e inmunología. Los autores repasan lo que hasta ahora se sabe de la patogénesis y la respuesta inmunitaria al virus de la rabia en los anfitriones infectados.

Introduction History of rabies control by vaccination. / Introduction History of rabies control by vaccination.

Since antiquity, rabies has remained one of the deadliest infectious diseases known to humankind, with a case fatality rate approaching 100% following the onset of clinical disease. It is present on all continents where terrestrial mammals exist, with the majority of animal and human cases being reported in the resourcelimited countries of Africa and Asia, with thousands of human rabies deaths being recorded annually. It is likely, however, that the global figure of approximately 59,000 annual human rabies fatalities is an underestimate. The impact of the disease has been reduced substantially across vast regions of the globe since the development of effective rabies vaccines. The success of different vaccines and vaccination policies in the defined 'at risk' populations has been born out of scientific innovation. Mass vaccination campaigns of animals, using parenteral vaccines to immunise companion animals, and advances in oral vaccines for wildlife, have allowed the elimination of rabies in terrestrial carnivores in several regions worldwide, including Western Europe and much of North America. In addition, human vaccines, largely used for post-exposure treatments, have reduced the burden of rabies in endemic areas.

La rage est depuis l'Antiquité l'une des maladies infectieuses faisant le plus de victimes humaines, avec un taux de létalité atteignant 100 % une fois les signes cliniques déclarés. La rage est présente sur tous les continents où existent des mammifères terrestres. La majorité des cas animaux et humains surviennent dans les pays à faibles revenus d'Afrique et d'Asie et des milliers de décès humains dus à la rage sont enregistrés chaque année dans le monde. Il est toutefois probable que les estimations mondiales d'environ 59 000 décès humains dus à la rage soient en-deçà de la réalité. L'impact de la maladie a fortement diminué dans de vastes régions du globe depuis la mise au point de vaccins efficaces. L'innovation scientifique a permis de développer plusieurs vaccins et d'appliquer avec succès des politiques de vaccination ciblant les populations définies comme « à risque ¼. Les campagnes de vaccination massive d'animaux par voie parentérale pour immuniser les animaux de compagnie et les progrès de la vaccination orale des animaux sauvages ont permis d'éliminer la rage chez les carnivores terrestres dans plusieurs régions du monde, dont l'Europe occidentale et une grande partie de l'Amérique du Nord. En outre, l'emploi systématique de vaccins humains pour les traitements post-exposition a allégé le fardeau de la rage dans les zones d'endémie.

La rabia ha sido desde tiempos antiguos, y sigue siendo aún hoy, una de las enfermedades infecciosas más mortíferas que ha conocido la humanidad, con una tasa de letalidad cercana al 100% una vez que ha entrado en su fase clínica. Está presente en todos los continentes que albergan mamíferos terrestres, si bien la mayoría de los casos de rabia humana y animal se declaran en países africanos y asiáticos con escasos recursos, donde la rabia mata cada año a miles de personas. Es probable, sin embargo, que el cálculo a escala mundial de unos 59 000 fallecimientos anuales por rabia humana esté por debajo de las cifras reales. Desde que existen vacunas antirrábicas eficaces, el impacto de la enfermedad ha menguado sensiblemente en vastas regiones del globo. El éxito obtenido con diferentes vacunas y políticas de vacunación en las poblaciones consideradas «expuestas¼ es deudor de la innovación científica. Las campañas de vacunación masiva de animales de compañía por vía parenteral y los avances en la vacunación oral de la fauna silvestre han servido para acabar con la rabia en las poblaciones de carnívoros terrestres de varias regiones del mundo, en particular Europa Occidental y gran parte de América del Norte. Además, las vacunas humanas, utilizadas principalmente como tratamiento tras la exposición, han reducido la carga de rabia en las zonas donde la enfermedad es endémica.

Assessing the impact of public education on a preventable zoonotic disease: rabies.

Effective methods to increase awareness of preventable infectious diseases are key components of successful control programmes. Rabies is an example of a disease with significant impact, where public awareness is variable. A recent awareness campaign in a rabies endemic region of Azerbaijan provided a unique opportunity to assess the efficacy of such campaigns. A cluster cross-sectional survey concerning rabies was undertaken following the awareness campaign in 600 households in 38 randomly selected towns, in districts covered by the campaign and matched control regions. This survey demonstrated that the relatively simple awareness campaign was effective at improving knowledge of rabies symptoms and vaccination schedules. Crucially, those in the awareness campaign group were also 1·4 times more likely to report that they had vaccinated their pets, an essential component of human rabies prevention. In addition, low knowledge of appropriate post-exposure treatment and animal sources of rabies provide information useful for future public awareness campaigns in the region and other similar areas.

Passive surveillance of United Kingdom bats for lyssaviruses (2005-2015).

Passive surveillance for lyssaviruses in UK bats has been ongoing since 1987 and has identified 13 cases of EBLV-2 from a single species; Myotis daubentonii. No other lyssavirus species has been detected. Between 2005 and 2015, 10 656 bats were submitted, representing 18 species, creating a spatially and temporally uneven sample of British bat fauna. Uniquely, three UK cases originate from a roost at Stokesay Castle in Shropshire, England, where daily checks for grounded and dead bats are undertaken and bat carcasses have been submitted for testing since 2007. Twenty per cent of Daubenton's bats submitted from Stokesay Castle since surveillance began, have tested positive for EBLV-2. Phylogenetic analysis reveals geographical clustering of UK viruses. Isolates from Stokesay Castle are more closely related to one another than to viruses from other regions. Daubenton's bats from Stokesay Castle represent a unique opportunity to study a natural population that appears to maintain EBLV-2 infection and may represent endemic infection at this site. Although the risk to public health from EBLV-2 is low, consequences of infection are severe and effective communication on the need for prompt post-exposure prophylaxis for anyone that has been bitten by a bat is essential.

First Complete Genomic Sequence of a Rabies Virus from the Republic of Tajikistan Obtained Directly from a Flinders Technology Associates Card.

A brain homogenate derived from a rabid dog in the district of Tojikobod, Republic of Tajikistan, was applied to a Flinders Technology Associates (FTA) card. A full-genome sequence of rabies virus (RABV) was generated from the FTA card directly without extraction, demonstrating the utility of these cards for readily obtaining genetic data.

Serological Detection of Antibodies to Peste des Petits Ruminants Virus in Large Ruminants.

Peste des petits ruminants (PPR) is an economically important disease of small ruminants with a rapidly expanding geographical distribution. Peste des petits ruminants virus may manifest in a variety of ways with disease ranging from acute to subclinical. We investigated the exposure of large ruminants to PPRV in areas where the virus is endemic in the small ruminant population by assessing the serological status of groups of animals. This study focused on the Punjab province of Pakistan as an area where the virus is endemic and where mixed farming practices occur enabling close interactions between small and large ruminant populations. An overall PPR seropositivity was detected in 10.0% of cattle and 14.16% of buffaloes. Following an assessment of serological profiles in large ruminants within different age groups, a maximum seroprevalence was observed in cattle (17.5%) and buffaloes (22.5%) over 2 years of age indicating the potential utility of sampling large ruminant populations for PPR serosurveillance. The large ruminants sampled between one and two years of age had similar levels of seropositivity within populations with 11.2% and 16.2% of animals being seropositive, respectively. Current PPR vaccination strategies do not enable the differentiation between infected and vaccinated small ruminants, and as such, the serological surveillance of sheep and goats is of little value. When considering eradication programmes for PPRV, this factor is of great significance. However, where large and small ruminants are farmed together, serological surveillance of large ruminants may provide a snapshot of virus infection within populations where mild disease is present or where small ruminants are regularly vaccinated.

Emergence of Lineage IV Peste des Petits Ruminants Virus in Ethiopia: Complete Genome Sequence of an Ethiopian Isolate 2010.

Isolates of peste des petits ruminants virus (PPRV) can be segregated genetically into four lineages. For decades, lineages I-III have been reported across Africa whilst lineage IV has predominantly circulated across Asia. However, the lineage distribution is currently changing in Africa. Importantly, full genome sequence data for African field isolates have been lacking. Here, we announce the first complete genome sequence of a field isolate of peste des petits ruminants virus (PPRV) from East Africa. This isolate was derived from the intestine of a goat suffering from severe clinical disease during the 2010 outbreak in Ethiopia. The full genome sequence of this isolate, PPRV Ethiopia/2010, clusters genetically with other lineage IV isolates of PPRV, sharing high levels of sequence identity across the genome. Further, we have carried out a phylogenetic analysis of all of the available African partial N gene and F gene PPRV sequences to investigate the epidemiology of PPRV with a focus on the emergence of different lineages of PPRV in Africa.

Peste des petits ruminants.

Peste des petits ruminants virus causes a highly infectious disease of small ruminants that is endemic across Africa, the Middle East and large regions of Asia. The virus is considered to be a major obstacle to the development of sustainable agriculture across the developing world and has recently been targeted by the World Organisation for Animal Health (OIE) and the Food and Agriculture Organisation (FAO) for eradication with the aim of global elimination of the disease by 2030. Fundamentally, the vaccines required to successfully achieve this goal are currently available, but the availability of novel vaccine preparations to also fulfill the requisite for differentiation between infected and vaccinated animals (DIVA) may reduce the time taken and the financial costs of serological surveillance in the later stages of any eradication campaign. Here, we overview what is currently known about the virus, with reference to its origin, updated global circulation, molecular evolution, diagnostic tools and vaccines currently available to combat the disease. Further, we comment on recent developments in our knowledge of various recombinant vaccines and on the potential for the development of novel multivalent vaccines for small ruminants.

Differential chemokine responses in the murine brain following lyssavirus infection.

The hallmark of lyssavirus infection is lethal encephalomyelitis. Previous studies have reported distinct lyssavirus isolate-related differences in severity of cellular recruitment into the encephalon in a murine model of infection following peripheral inoculation with rabies virus (RABV) and European bat lyssavirus (EBLV)-1 and -2. In order to understand the role of chemokines in this process, comparative studies of the chemokine pattern, distribution and production in response to infection with these lyssaviruses were undertaken. Expression of CCL2, CCL5 and CXCL10 was observed throughout the murine brain with a distinct caudal bias in distribution, similar to both inflammatory changes and virus antigen distribution. CCL2 immunolabelling was localized to neuronal and astroglial populations. CCL5 immunolabelling was only detected in the astroglia, while CXCL10 labelling, although present in the astroglia, was more prominent in neurons. Isolate-dependent differences in the amount of chemokine immunolabelling in specific brain regions and chemokine production by neurons in vitro were observed, with a greater expression of CCL5 in vivo and CXCL10 production in vitro after EBLV infection. Additionally, strong positive associations between chemokine immunolabelling and perivascular cuffing and, to a lesser extent, virus antigen score were also observed. These differences in chemokine expression may explain the variation in severity of encephalitic changes observed in animals infected with different lyssavirus isolates.

Pathobiology of rabies virus and the European bat lyssaviruses in experimentally infected mice.

A comparison of the clinicopathology of European bat lyssavirus (EBLV) types-1 and -2 and of rabies virus was undertaken. Following inoculation of mice at a peripheral site with these viruses, clinical signs of rabies and distribution of virus antigen in the mouse brain were examined. The appearance of clinical signs of disease varied both within and across the different virus species, with variation in incubation periods and weight loss throughout disease progression. The distribution of viral antigen throughout the regions of the brain examined was similar for each of the isolates during the different stages of disease progression, suggesting that antigen distribution was not associated with clinical presentation. However, specific regions of the brain including the cerebellum, caudal medulla, hypothalamus and thalamus, showed notable differences in the proportion of virus antigen positive cells present in comparison to other brain regions suggesting that these areas are important in disease development irrespective of virus species.

The Plowright vaccine strain of Rinderpest virus has attenuating mutations in most genes.

The currently used vaccine strain of Rinderpest virus was derived by serial passage of the highly virulent Kabete 'O' strain (KO). A full-length cDNA copy of the KO strain was made from which a virus identical in pathogenicity to the wild-type virus was rescued. A series of chimeric viruses was prepared in which the coding sequences for the N, P, F, H or L proteins were replaced with the corresponding sequences from the vaccine strain. The KO-based virus with the vaccine strain H gene and that with the carboxy-terminal half of the L gene replaced with the corresponding sequence from the vaccine strain retained all or almost all of the virulence of the original KO virus. Animals infected with the KO-based virus containing the vaccine strain N, P or F gene, or the amino-terminal half of the L gene, developed high and prolonged pyrexia and leukopenia, but with reduced or absent lesions and other clinical signs; although partially attenuated, none was nearly as attenuated as the vaccine strain itself. These data indicate that the high attenuation and stability of the current vaccine are due to the accumulation of a number of separate mutations, none of which is itself so sufficiently debilitating that there is strong selective pressure in favour of the revertant.

Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling.

Linear and convergent routes for the large-scale preparation of the hematoregulatory nonapeptide (Glp-Glu-Asp)2-DAS-(Lys)2 (2, SK&F 107647) were investigated. A convergent approach ('3 + 2'-route employing Boc-and benzyl ester protecting groups) was selected for the preparation of multihundred-gram quantities of 2. Key steps were the preparation and the coupling of tripeptide hydrochloride (HCl.H)2-DAS-(Lys(Z)-OBn)2 (6, DAS-2,7-L,L-diaminosuberic acid) and tripeptide Glp-Glu(OBn)-Asp(OBn)-OH (26). Several coupling reagents were investigated in order to reduce the amount of epimerization of this fragment coupling. TDBTU [O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl-1,1,3,3-tetrameth yluronium tetrafluoroborate] was identified as the condensation reagent of choice. Using this synthetic route > 97% pure final product in an overall yield of 35% calculated on di-Boc protected 2,7-L,L-diaminosuberic acid was prepared.