Rinderpest: A Disease of the Past, and a Present Threat.

Rinderpest is a highly contagious viral disease that affects ungulates such as cattle, buffalo, yak, and various wildlife species, leading to significant morbidity and mortality. The global eradication of rinderpest was successfully accomplished in 2011 through extensive vaccination efforts. Today, safeguarding against the re-emergence of rinderpest in animal populations is paramount. The Food and Agriculture Organization of the United Nations and the World Organization for Animal Health are entrusted through a series of resolutions with the responsibility to prevent the re-emergence of rinderpest in animals.

History of measles.

Measles is a highly contagious viral disease transmitted by aerosols through human-to-human contact. It is often considered as a benign disease, although mortality remains high in developing countries (>5%). Frequent complications (diarrhea, otitis, pneumonia, encephalitis) can be observed. The disease mainly affects young children from 5 to 6 months of age with a mortality peak in the first three years of life. The Persian physician Rhazes gave the first clinical description of the disease in the 10th century, clearly differentiating it from smallpox. Measles spread worldwide from the Renaissance. Its epidemiology was remarkably studied in 1846 by a Danish physician, Peter Panum, during an epidemic in the Faroe Islands. The viral nature of this disease was demonstrated in 1911 and the virus was identified in 1954 by Thomas Peebles and John Enders. It is a morbillivirus (family Paramyxoviridae), also responsible for rinderpest (ovine, bovine), distemper (canine, feline), and epidemic diseases of dolphins, porpoises and seals. The current measles virus appeared recently from the rinderpest virus around the 6th century BCE. It has adapted perfectly to the human species, becoming strictly human, without animal reservoirs. A live attenuated vaccine was developed in 1958 by Enders' team after numerous passages in cell cultures. The vaccine was licensed in the United States in 1963 and is used on a large scale by the WHO throughout the world. This highly effective and well-tolerated vaccine has greatly reduced the number of measles cases and saved millions of lives. Measles remains a major public health concern, causing over 100,000 deaths per year worldwide. Today, the most affected continents remain Africa, South America and Asia.

Sequestration and Destruction of Rinderpest Virus-Containing Material 10 Years after Eradication.

In 2021, the world marked 10 years free from rinderpest. The United Nations Food and Agriculture Organization and World Organisation for Animal Health have since made great strides in consolidating, sequencing, and destroying stocks of rinderpest virus-containing material, currently kept by only 14 known institutions. This progress must continue.

Measles virus and rinderpest virus divergence dated to the sixth century BCE.

Many infectious diseases are thought to have emerged in humans after the Neolithic revolution. Although it is broadly accepted that this also applies to measles, the exact date of emergence for this disease is controversial. We sequenced the genome of a 1912 measles virus and used selection-aware molecular clock modeling to determine the divergence date of measles virus and rinderpest virus. This divergence date represents the earliest possible date for the establishment of measles in human populations. Our analyses show that the measles virus potentially arose as early as the sixth century BCE, possibly coinciding with the rise of large cities.

Full genome sequencing of archived wild type and vaccine rinderpest virus isolates prior to their destruction.

When rinderpest virus (RPV) was declared eradicated in 2011, the only remaining samples of this once much-feared livestock virus were those held in various laboratories. In order to allow the destruction of our institute's stocks of RPV while maintaining the ability to recover the various viruses if ever required, we have determined the full genome sequence of all our distinct samples of RPV, including 51 wild type viruses and examples of three different types of vaccine strain. Examination of the sequences of these virus isolates has shown that the African isolates form a single disparate clade, rather than two separate clades, which is more in accord with the known history of the virus in Africa. We have also identified two groups of goat-passaged viruses which have acquired an extra 6 bases in the long untranslated region between the M and F protein coding sequences, and shown that, for more than half the genomes sequenced, translation of the F protein requires translational frameshift or non-standard translation initiation. Curiously, the clade containing the lapinised vaccine viruses that were developed originally in Korea appears to be more similar to the known African viruses than to any other Asian viruses.

New world origin of canine distemper: Interdisciplinary insights.

OBJECTIVE: Canine distemper virus (CDV), human measles virus (HMV), and rinderpest virus (RPV) of cattle are morbilliviruses that have caused devastating outbreaks for centuries. This paper seeks to reconstruct the evolutionary history of CDV. MATERIALS AND METHODS: An interdisciplinary approach is adopted, synthesizing paleopathological analysis of 96 Pre-Columbian dogs (750-1470 CE) from the Weyanoke Old Town, Virginia site, with historical reports, molecular analysis and morbilliviral epidemiology. RESULTS: Both measles (c.900CE) and rinderpest (c. 376 BCE) were first reported in Eurasia, while canine distemper was initially described in South America much later (1735 CE); there are no paleopathological indications of CDV in Weyanoke Old Town dogs. Molecularly, CDV is closely related to HMV, while viral codon usage indicates CDV may have previously infected humans; South American measles epidemics occurred prior to the emergence of canine distemper and would have facilitated HMV transmission and adaptation to dogs. CONCLUSIONS: The measles epidemics that decimated indigenous South American populations in the 1500-1700 s likely facilitated the establishment of CDV as a canine pathogen, which eventually spread to Europe and beyond. SIGNIFICANCE: Understanding the historical and environmental conditions that have driven morbilliviral evolution provides important insights into potential future threats of animal/human cross-species infections. LIMITATIONS: Interpreting historical disease descriptions is difficult and the archaeological specimens are limited. Molecular sequence data and codon usage analyses rely on modern viruses. SUGGESTIONS FOR FURTHER RESEARCH: Interdisciplinary approaches are increasingly needed to understand diseases of the past and present, as critical information and knowledge is scattered in different disciplines.

Analyses of nucleotide, codon and amino acids usages between peste des petits ruminants virus and rinderpest virus.

Peste des petits ruminants virus (PPRV) and rinderpest virus (RPV) are two causative agents of an economically important disease for ruminants (i.e., sheep, cattle and goat). In this study, the nucleotide, codon and amino acid usages for PPRV and RPV have been analyzed by multivariate statistical methods. Relative synonymous codon usage (RSCU) analysis represents that ACG for Thr and GCG for Ala are selected with under-representation in both PPRV and RPV, and AGA for Arg in PPRV and AGG for Arg in RPV are used with over-representation. The usage of nucleotide pair (CpG) tends to be removed from viral genes of the two viruses, suggesting that other evolutionary forces take part in evolutionary processes for viral genes in addition to mutation pressure from nucleotide usage at the third codon position. The overall nucleotide usage of viral gene is not major factor in shaping synonymous codon usage patterns, while the nucleotide usages at the third codon position and the nucleotide pairs play important roles in shaping synonymous codon usage patterns. Although PPRV and RPV are closely related antigenically, the codon and amino acid usage patterns for viral genes represent a significant genetic diversity between PPRV and RPV. Moreover, the overall codon usage trends for viral genes between PPRV and RPV are mainly influenced by mutation pressure from nucleotide usage at the third codon position and translation selection from hosts. Taken together, this is first comprehensive analyses for nucleotide, codon and amino acid usages of viral genes of PPRV and RPV and the findings are expected to increase our understanding of evolutionary forces influencing viral evolutionary pathway and adaptation toward hosts.

Rinderpest eradication: challenges for remaining disease free and implications for future eradication efforts.

In 2011, the World Organisation for Animal Health (OIE) and the Food and Agriculture Organization of the United Nations (FAO) declared global freedom from rinderpest, formally announcing that rinderpest virus infections had been eliminated from susceptible livestock populations. At the same time, it was recognised that rinderpest virus, and material containing rinderpest virus, remained stored in an unspecified number of facilities across the world. Although natural infections had been eliminated, there remained a risk that rinderpest could reoccur if such infectious material accidentally leaked or was intentionally released from one of these facilities into a susceptible animal population. To minimise this risk, the OIE and FAO, with the support of international partners, set in place a framework to: reduce the quantity of remaining rinderpest-virus-containing material; ensure that such material was only stored in high-security facilities; regulate any handling or manipulation of the virus; maintain vigilance amongst livestock keepers and Veterinary Services in the post-eradication era; and develop contingency plans to deal with any suspected or actual reoccurrence of rinderpest disease. In 2016, five years after the declaration of global freedom from rinderpest, official reports to the OIE show that virus and virus-containing material remain stored in 21 countries worldwide in 22 separate facilities, of which only five have been inspected and approved for holding rinderpest virus or vaccine. There is still much work to be done to further reduce the risk of a reoccurrence.

En 2011, l'Organisation mondiale de la santé animale (OIE) et l'Organisation des Nations Unies pour l'alimentation et l'agriculture (FAO) ont annoncé officiellement l'élimination de l'infection due au virus de la peste bovine dans les populations d'animaux d'élevage sensibles, déclarant ainsi la planète indemne de cette maladie. Parallèlement, les deux organisations faisaient état de l'existence d'un nombre indéterminé d'établissements dans le monde détenant des stocks du virus bovipestique ainsi que des produits contenant ce virus. Malgré l'élimination de l'infection chez ses hôtes naturels, un risque de réapparition de la peste bovine subsiste en cas de fuite accidentelle ou d'émission délibérée de ces produits infectieux dans les populations animales sensibles à partir de l'un de ces établissements. Afin de minimiser ce risque, l'OIE et la FAO soutenus par leurs partenaires internationaux ont mis en place un cadre visant plusieurs objectifs : réduire les quantités restantes de produits contenant le virus de la peste bovine dans le monde ; veiller à ce que ces produits ne soient stockés que dans des établissements de haute sécurité ; réglementer les conditions de détention et de manipulation du virus ; poursuivre la surveillance exercée par les éleveurs et les Services vétérinaires au cours de la phase post-éradication ; concevoir des plans d'urgence visant à faire face à toute réapparition suspectée ou confirmée de la peste bovine. En 2016, soit cinq ans après la déclaration de l'éradication mondiale de la peste bovine, il ressort des rapports officiels adressés à l'OIE que 21 pays détiennent encore des stocks du virus de la peste bovine ou des produits contenant ce virus, répartis en 22 établissements distincts dont seulement cinq ont fait l'objet d'une inspection et ont été dûment habilités à détenir des stocks de virus de la peste bovine ou de vaccins contre cette maladie. Il reste donc encore beaucoup à faire pour continuer à réduire le risque de réapparition de la peste bovine.

En 2011, la Organización Mundial de Sanidad Animal (OIE) y la Organización de las Naciones Unidas para la Alimentación y la Agricultura (FAO) anunciaron oficialmente que las infecciones causadas por el virus de la peste bovina habían sido eliminadas de las poblaciones sensibles de ganado, declarando así que el mundo quedaba libre de la enfermedad. Al mismo tiempo, significaron que un número no especificado de instalaciones dispersas por el mundo albergaban muestras del virus y otros productos que lo contenían. Aunque las infecciones naturales habían quedado eliminadas, subsistía el riesgo de reaparición de la peste bovina si en una de esas instalaciones se producía una fuga accidental o una liberación intencionada de material infeccioso y este entraba en contacto con una población animal sensible. Para reducir al mínimo tal riesgo, la OIE y la FAO, con apoyo de colaboradores internacionales, definieron un dispositivo encaminado a: reducir el volumen de material restante con contenido viral de la peste bovina; garantizar que ese material fuera conservado únicamente en instalaciones de alta seguridad; reglamentar toda manipulación del virus; mantener la vigilancia entre cuidadores de ganado y Servicios Veterinarios en el periodo posterior a la erradicación; y elaborar planes de emergencia para responder a toda reaparición, presunta o confirmada, de la peste bovina. En 2016, cinco años después de la declaración de ausencia mundial de peste bovina, los informes oficiales remitidos a la OIE daban fe de que había virus y productos que lo contenían en 22 instalaciones situadas en 21 países del mundo, de las que solo cinco habían sido inspeccionadas y homologadas para albergar virus de la peste bovina o vacunas contra la enfermedad. Queda pues mucho trabajo por delante para reducir en mayor medida el riesgo de reaparición.

Enhanced immunosurveillance for animal morbilliviruses using vesicular stomatitis virus (VSV) pseudotypes.

The measurement of virus-specific neutralising antibodies represents the "gold-standard" for diagnostic serology. For animal morbilliviruses, such as peste des petits ruminants (PPRV) or rinderpest virus (RPV), live virus-based neutralisation tests require high-level biocontainment to prevent the accidental escape of the infectious agents. In this study, we describe the adaptation of a replication-defective vesicular stomatitis virus (VSVΔG) based pseudotyping system for the measurement of neutralising antibodies against animal morbilliviruses. By expressing the haemagglutinin (H) and fusion (F) proteins of PPRV on VSVΔG pseudotypes bearing a luciferase marker gene, neutralising antibody titres could be measured rapidly and with high sensitivity. Serological responses against the four distinct lineages of PPRV could be measured simultaneously and cross-neutralising responses against other morbilliviruses compared. Using this approach, we observed that titres of neutralising antibodies induced by vaccination with live attenuated PPRV were lower than those induced by wild type virus infection and the level of cross-lineage neutralisation varied between vaccinates. By comparing neutralising responses from animals infected with either PPRV or RPV, we found that responses were highest against the homologous virus, indicating that retrospective analyses of serum samples could be used to confirm the nature of the original pathogen to which an animal had been exposed. Accordingly, when screening sera from domestic livestock and wild ruminants in Tanzania, we detected evidence of cross-species infection with PPRV, canine distemper virus (CDV) and a RPV-related bovine morbillivirus, suggesting that exposure to animal morbilliviruses may be more widespread than indicated previously using existing diagnostic techniques.

The RNA triphosphatase domain of L protein of Rinderpest virus exhibits pyrophosphatase and tripolyphosphatase activities.

L protein of the Rinderpest virus, an archetypal paramyxovirus possesses RNA-dependent RNA polymerase activity which transcribes the genome into mRNAs as well as replicates the RNA genome. The protein also possesses RNA triphosphatase (RTPase), guanylyltransferase (GTase) and methyltransferase enzyme activities responsible for capping the mRNAs in a conventional pathway similar to that of the host pathway. Subsequent to the earlier characterization of the GTase activity of L protein and identification of the RTPase domain of the L protein, we report here, additional enzymatic activities associated with the RTPase domain. We have characterized the pyrophosphatase and tripolyphosphatase activities of the L-RTPase domain which are metal-dependent and proceed much faster than the RTPase activity. Interestingly, the mutant proteins E1645A and E1647A abrogated the pyrophosphatase and tripolyphosphatase significantly, indicating a strong overlap of the active sites of these activities with that of RTPase. We discuss the likely role of GTase-associated L protein pyrophosphatase in the polymerase function. We also discuss a possible biological role for the tripolyphosphatase activity hitherto considered insignificant for the viruses possessing such activity.

Protection of Cattle against Rinderpest by Vaccination with Wild-Type but Not Attenuated Strains of Peste des Petits Ruminants Virus.

UNLABELLED: Although rinderpest virus (RPV) has been eradicated in the wild, efforts are still continuing to restrict the extent to which live virus is distributed in facilities around the world and to prepare for any reappearance of the disease, whether through deliberate or accidental release. In an effort to find an alternative vaccine which could be used in place of the traditional live attenuated RPV strains, we have determined whether cattle can be protected from rinderpest by inoculation with vaccine strains of the related morbillivirus, peste des petits ruminants virus (PPRV). Cattle were vaccinated with wild-type PPRV or either of two established PPRV vaccine strains, Nigeria/75/1 or Sungri/96. All animals developed antibody and T cell immune responses to the inoculated PPRV. However, only the animals given wild-type PPRV were protected from RPV challenge. Animals given PPRV/Sungri/96 were only partially protected, and animals given PPRV/Nigeria/75/1 showed no protection against RPV challenge. While sera from animals vaccinated with the vaccine strain of RPV showed cross-neutralizing ability against PPRV, none of the sera from animals vaccinated with any strain of PPRV was able to neutralize RPV although sera from animals inoculated with wild-type PPRV were able to neutralize RPV-pseudotyped vesicular stomatitis virus. IMPORTANCE: Rinderpest virus has been eradicated, and it is only the second virus for which this is so. Significant efforts are still required to ensure preparedness for a possible escape of RPV from a laboratory or its deliberate release. Since RPV vaccine protects sheep and goats from PPRV, it is important to determine if the reverse is true as this would provide a non-RPV vaccine for dealing with suspected RPV outbreaks. This is probably the last in vivo study with live RPV that will be approved.

Specific detection of peste des petits ruminants virus antibodies in sheep and goat sera by the luciferase immunoprecipitation system.

Peste des petits ruminants (PPR) is a contagious and often fatal transboundary animal disease affecting mostly sheep, goats and wild small ruminants. This disease is endemic in most of Africa, the Middle, Near East, and large parts of Asia. The causal agent is peste des petits ruminants virus (PPRV), which belongs to the genus Morbillivirus in the family Paramyxoviridae. This genus also includes measles virus (MV), canine distemper virus (CDV) and rinderpest virus (RPV). All are closely related viruses with serological cross reactivity. In this study, we have developed a Luciferase Immunoprecipitation System (LIPS) for the rapid detection of antibodies against PPRV in serum samples and for specific differentiation from antibodies against RPV. PPR and rinderpest (RP) serum samples were assayed by PPR-LIPS and two commercially available PPR cELISA tests. The PPR-LIPS showed high sensitivity and specificity for the samples tested and showed no cross reactivity with RPV unlike the commercial PPR cELISA tests which did cross react with RPV. Based on the results shown in this study, PPR-LIPS is presented as a good candidate for the specific serosurveillance of PPR.

Identifying and Reducing Remaining Stocks of Rinderpest Virus.

In 2011, the world was declared free from rinderpest, one of the most feared and devastating infectious diseases of animals. Rinderpest is the second infectious disease, after smallpox, to have been eradicated. However, potentially infectious rinderpest virus material remains widely disseminated among research and diagnostic facilities across the world and poses a risk for disease recurrence should it be released. Member Countries of the World Organisation for Animal Health and the Food and Agricultural Organization of the United Nations are committed to destroying remaining stocks of infectious material or ensuring that it is stored under international supervision in a limited number of approved facilities. To facilitate this commitment and maintain global freedom from rinderpest, World Organisation for Animal Health Member Countries must report annually on rinderpest material held in their countries. The first official surveys, conducted during 2013-2015, revealed that rinderpest material was stored in an unacceptably high number of facilities and countries.

Evidence for N7 guanine methyl transferase activity encoded within the modular domain of RNA-dependent RNA polymerase L of a Morbillivirus.

Post-transcriptional modification of viral mRNA is essential for the translation of viral proteins by cellular translation machinery. Due to the cytoplasmic replication of Paramyxoviruses, the viral-encoded RNA-dependent RNA polymerase (RdRP) is thought to possess all activities required for mRNA capping and methylation. In the present work, using partially purified recombinant RNA polymerase complex of rinderpest virus expressed in insect cells, we demonstrate the in vitro methylation of capped mRNA. Further, we show that a recombinant C-terminal fragment (1717-2183 aa) of L protein is capable of methylating capped mRNA, suggesting that the various post-transcriptional activities of the L protein are located in independently folding domains.

A carboxy terminal domain of the L protein of rinderpest virus possesses RNA triphosphatase activity - The first enzyme in the viral mRNA capping pathway.

The large protein L of negative-sense RNA viruses is a multifunctional protein involved in transcription and replication of genomic RNA. It also possesses enzymatic activities involved in capping and methylation of viral mRNAs. The pathway for mRNA capping followed by the L protein of the viruses in the Morbillivirus genus has not been established, although it has been speculated that these viruses may follow the unconventional capping pathway as has been shown for some viruses of Rhabdoviridae family. We had earlier shown that the large protein L of Rinderpest virus expressed as recombinant L-P complex in insect cells as well as the ribonucleoprotein complex from purified virus possesses RNA triphosphatase (RTPase) and guanylyltransferase activities, in addition to RNA dependent RNA polymerase activity. In the present work, we demonstrate that RTPase as well as nucleoside triphosphatase (NTPase) activities are exhibited by a subdomain of the L protein in the C terminal region (a.a. 1640-1840). The RTPase activity depends absolutely on a divalent cation, either magnesium or manganese. Both the RTPase and NTPase activities of the protein show dual metal specificity. Two mutant proteins having alanine mutations in the glutamic acid residues in motif-A of the RTPase domain did not show RTPase activity, while exhibiting reduced NTPase activity suggesting overlapping active sites for the two enzymatic functions. The RTPase and NTPase activities of the L subdomain resemble those of the Vaccinia capping enzyme D1 and the baculovirus LEF4 proteins.

Morbillivirus vaccines: recent successes and future hopes.

The impact of morbilliviruses on both human and animal populations is well documented in the history of mankind. Indeed, prior to the development of vaccines for these diseases, morbilliviruses plagued both humans and their livestock that were heavily relied upon for food and motor power within communities. Measles virus (MeV) was responsible for the death of millions of people annually across the world and those fortunate enough to escape the disease often faced starvation where their livestock had died following infection with rinderpest virus (RPV) or peste des petits ruminants virus (PPRV). Canine distemper virus has affected dog populations for centuries and in the past few decades appears to have jumped species, now causing disease in a number of non-canid species, some of which are been pushed to the brink of extinction by the virus. During the age of vaccination, the introduction and successful application of vaccines against rinderpest and measles has led to the eradication of the former and the greater control of the latter. Vaccines against PPR and canine distemper have also been generated; however, the diseases still pose a threat to susceptible species. Here we review the currently available vaccines against these four morbilliviruses and discuss the prospects for the development of new generation vaccines.