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.

[Effects of the periodical spread of rinderpest on famine, epidemic, and tiger disasters in the late 17th Century].

This study clarifies the causes of the repetitive occurrences of such phenomena as rinderpest, epidemic, famine, and tiger disasters recorded in the Joseon Dynasty Chronicle and the Seungjeongwon Journals in the period of great catastrophe, the late 17th century in which the great Gyeongsin famine (1670~1671) and the great Eulbyeong famine (1695~1696) occurred, from the perspective that they were biological exchanges caused by the new arrival of rinderpest in the early 17th century. It is an objection to the achievements by existing studies which suggest that the great catastrophes occurring in the late 17th century are evidence of phenomena in a little ice age. First of all, rinderpest has had influence on East Asia as it had been spread from certain areas in Machuria in May 1636 through Joseon, where it raged throughout the nation, and then to the west part of Japan. The new arrival of rinderpest was indigenized in Joseon, where it was localized and spread periodically while it was adjusted to changes in the population of cattle with immunity in accordance with their life spans and reproduction rates. As the new rinderpest, which showed high pathogenicity in the early 17th century, was indigenized with its high mortality and continued until the late 17th century, it broke out periodically in general. Contrastively, epidemics like smallpox and measles that were indigenized as routine ones had occurred constantly from far past times. As a result, the rinderpest, which tried a new indigenization, and the human epidemics, which had been already indigenized long ago, were unexpectedly overlapped in their breakout, and hence great changes were noticed in the aspects of the human casualty due to epidemics. The outbreak of rinderpest resulted in famine due to lack of farming cattle, and the famine caused epidemics among people. The casualty of the human population due to the epidemics in turn led to negligence of farming cattle, which constituted factors that triggered rage and epidemics of rinderpest. The more the number of sources of infection and hosts with low immunity increased, the more lost human resources and farming cattle were lost, which led to a great famine. The periodic outbreak of the rinderpester along with the routine prevalence of various epidemics in the 17thcentury also had influenced on domestic and wild animals. Due to these phenomenon, full-fledged famines occurred that were incomparable with earlier ones. The number of domestic animals that were neglected by people who, faced with famines, were not able to take care of them was increased, and this might have brought about the rage of epidemics like rinderpest in domestic animals like cattle. The great Gyeongsin and Eulbyeong famines due to reoccurrence of the rinderpest in the late 17th century linked rinderpester, epidemics and great famines so that they interacted with each other. Furthermore, the recurring cycle of epidemics-famines-rinderpest-great famines constituted a great cycle with synergy, which resulted in eco-economic-historical great catastrophes accompanied by large scale casualties. Therefore, the Gyeongsin and Eulbyeong famines occurring in the late 17th century can be treated as events caused by the repetition of various periodic disastrous factors generated in 1670~1671 and in 1695~1696 respectively, and particularly as phenomena caused by biological exchanges based on rinderpester., rather than as little ice age phenomena due to relatively long term temperature lowering.

The risk of rinderpest re-introduction in post-eradication era.

In 2011, ten years after the last reported outbreak, the eradication of rinderpest was declared. However, as rinderpest virus stocks still exist, there remains a risk of rinderpest re-introduction. A semi-quantitative risk assessment was conducted to assess this risk, which was defined as the probability of at least one host becoming infected and infectious outside a laboratory anywhere in the world within a one-year period. Pathways leading to rinderpest re-introduction were: deliberate or accidental use of virus in laboratories, deliberate or accidental use of vaccines, host exposure to an environmental source of virus, and use of virus for anti-animal biological warfare. The probability of each pathway step occurring was estimated through expert opinion elicitation. The risk estimate was associated with a high degree of uncertainty. It was estimated to range from negligible to high, with the median being very low. The accidental use of laboratory virus stocks was the highest risk pathway. Reducing the number of virus stocks and restricting their use, as well as upgrading the laboratories to a higher biosafety level, would effectively decrease the maximum and median risks. Likewise, ensuring that remaining vaccine stocks are not used and are instead destroyed or relocated to a limited number of regional repositories would also have a major effect on these estimates. However, these measures are unlikely to eliminate the risk of rinderpest re-introduction so that maintaining response preparedness is essential.

Different functions of the common P/V/W and V-specific domains of rinderpest virus V protein in blocking IFN signalling.

The V proteins of paramyxoviruses are composed of two evolutionarily distinct domains, the N-terminal 75 % being common to the viral P, V and W proteins, and not highly conserved between viruses, whilst the remaining 25 % consists of a cysteine-rich V-specific domain, which is conserved across almost all paramyxoviruses. There is evidence supporting a number of different functions of the V proteins of morbilliviruses in blocking the signalling pathways of type I and II IFNs, but it is not clear which domains of V are responsible for which activities and whether all these activities are required for effective blockade of IFN signalling. We have shown here that the two domains of rinderpest virus V protein have distinct functions: the N-terminal domain acted to bind STAT1, whilst the C-terminal V-specific domain interacted with the IFN receptor-associated kinases Jak1 and Tyk2. Effective blockade of IFN signalling required the intact V protein.

Modelling the expected rate of laboratory biosafety breakdowns involving rinderpest virus in the post-eradication era.

Now that we are in the rinderpest post-eradication era, attention is focused on the risk of re-introduction. A semi-quantitative risk assessment identified accidental use of rinderpest virus in laboratories as the most likely cause of re-introduction. However there is little data available on the rates of laboratory biosafety breakdowns in general. In addition, any predictions based on past events are subject to various uncertainties. The aims of this study were therefore to investigate the potential usefulness of historical data for predicting the future risk of rinderpest release via laboratory biosafety breakdowns, and to investigate the impacts of the various uncertainties on these predictions. Data were collected using a worldwide online survey of laboratories, a structured search of ProMED reports and discussion with experts. A stochastic model was constructed to predict the number of laboratory biosafety breakdowns involving rinderpest that will occur over the next 10 years, based on: (1) the historical rate of biosafety breakdowns; and (2) the change in the number of laboratories that will have rinderpest virus in the next 10 years compared to historically. The search identified five breakdowns, all of which occurred during 1970-2000 and all of which were identified via discussions with experts. Assuming that our search for historical events had a sensitivity of over 60% and there has been at least a 40% reduction in the underlying risk (attributable to decreased laboratory activity post eradication) the most likely number of biosafety events worldwide was estimated to be zero over a 10 year period. However, the risk of at least one biosafety breakdown remains greater than 1 in 10,000 unless the sensitivity was at least 99% or the number of laboratories has decreased by at least 99% (based on 2000-2010 during which there were no biosafety breakdowns).

Rinderpest virus sequestration and use in posteradication era.

After the 2011 declaration of rinderpest disease eradication, we surveyed 150 countries about rinderpest virus stocks. Forty-four laboratories in 35 countries held laboratory-attenuated strains, field strains, or diagnostic samples. Vaccine and reagent production and laboratory experiments continued. Rigorous standards are necessary to ensure that stocks are kept under safe conditions.

[Morbilliviruses].

The genus Morbillivirus in the family Paramyxoviridae contains many pathogens, which are important for medicine or veterinary medicine. Because each morbillivirus has restricted host range and serologically monotypic, the virus infection and transmission is effectively controlled by vaccinations and surveillance. Rinderpest virus has been eradicated in 2011, and elimination of measles virus progresses worldwide. Recently, a new cell receptor for measles virus, nectin4 was identified. Both SLAM, a molecule expressing on immune cells, and nectin4, a molecule expressing on epithelial cells, are important to infectivity and pathogenicity of the virus.

Recombinant vaccines against the mononegaviruses--what we have learned from animal disease controls.

The mononegaviruses include a number of highly contagious and severe disease-causing viruses of both animals and humans. For the control of these viral diseases, development of vaccines, either with classical methods or with recombinant DNA virus vectors, has been attempted over the years. Recently reverse genetics of mononegaviruses has been developed and used to generate infectious viruses possessing genomes derived from cloned cDNA in order to study the consequent effects of viral gene manipulations on phenotype. This technology allows us to develop novel candidate vaccines. In particular, a variety of different attenuation strategies to produce a range of attenuated mononegavirus vaccines have been studied. In addition, because of their ideal nature as live vaccines, recombinant mononegaviruses expressing foreign proteins have also been produced with the aim of developing multivalent vaccines against more than one pathogen. These recombinant mononegaviruses are currently under evaluation as new viral vectors for vaccination. Reverse genetics could have great potential for the preparation of vaccines against many mononegaviruses.

Characterization of the complete genomic sequence of the rinderpest virus Fusan strain cattle type, which is the most classical isolate in Asia and comparison with its lapinized strain.

In this study, we characterized the rinderpest virus (RPV) Fusan strain cattle type (B), which is the most classical isolate in Asia, by complete genomic sequence analysis and compared it with its lapinized Nakamura III (L) strain. The transversion rates of the M, F, and H genes were higher than those of other genes. In contrast, the deduced amino acid (aa) substitution rates of the P, C, and V genes were higher than those of other genes, although their transversion rates were not higher. The characteristic nucleotide (nt) or aa residues of the cattle-virulent B and Kabete 'O' strains were observed in the P/C/V, M, and L genes. According to these results, we speculate that nt/aa substitution in the P/C/V genes is one of the key determinants for the difference in the pathogenicity to cattle of the B and L strains.

Disease properties, geography, and mitigation strategies in a simulation spread of rinderpest across the United States.

For the past decade, the Food and Agriculture Organization of the United Nations has been working toward eradicating rinderpest through vaccination and intense surveillance by 2012. Because of the potential severity of a rinderpest epidemic, it is prudent to prepare for an unexpected outbreak in animal populations. There is no immunity to the disease among the livestock or wildlife in the United States (US). If rinderpest were to emerge in the US, the loss in livestock could be devastating. We predict the potential spread of rinderpest using a two-stage model for the spread of a multi-host infectious disease among agricultural animals in the US. The model incorporates large-scale interactions among US counties and the small-scale dynamics of disease spread within a county. The model epidemic was seeded in 16 locations and there was a strong dependence of the overall epidemic size on the starting location. The epidemics were classified according to overall size into small epidemics of 100 to 300 animals (failed epidemics), epidemics infecting 3,000 to 30,000 animals (medium epidemics), and the large epidemics infecting around one million beef cattle. The size of the rinderpest epidemics were directly related to the origin of the disease and whether or not the disease moved into certain key counties in high-livestock-density areas of the US. The epidemic size also depended upon response time and effectiveness of movement controls.

Simultaneous detection of Rift Valley Fever, bluetongue, rinderpest, and Peste des petits ruminants viruses by a single-tube multiplex reverse transcriptase-PCR assay using a dual-priming oligonucleotide system.

The aim of this study was to develop a highly sensitive and specific one-step multiplex reverse transcriptase PCR assay for the simultaneous and differential detection of Rift Valley Fever virus (RVFV), bluetongue virus (BTV), rinderpest virus (RPV), and Peste des petits ruminants virus (PPRV). These viruses cause mucosal lesions in cattle, sheep, and goats, and they are difficult to differentiate from one another based solely on their clinical presentation in suspected disease cases. In this study, we developed a multiplex reverse transcriptase PCR to detect these viruses using a novel dual-priming oligonucleotide (DPO). The DPO contains two separate priming regions joined by a polydeoxyinosine linker, which blocks extension of nonspecifically primed templates and consistently allows high PCR specificity even under less-than-optimal PCR conditions. A total of 19 DPO primers were designed to detect and discriminate between RVFV, BTV, RPV, and PPRV by the generation of 205-, 440-, 115-, and 243-bp cDNA products, respectively. The multiplex reverse transcriptase PCR described here enables the early diagnosis of these four viruses and may also be useful as part of a testing regime for cattle, sheep, or goats exhibiting similar clinical signs, including mucosal lesions.

Genetic characterization of the Korean LATC06 rinderpest vaccine strain.

We sequenced the genome of LATC06 generated by in vitro passage in Vero cells of the lapinized-avianized (LA) strain and compared its sequence to those of other rinderpest viruses. The LATC06 genome consists of 15882 nucleotides. Its transcriptional regulatory control sequences (TRSs) at gene boundaries are identical to those of the Kabete O strain. Cleavage sites for generating F1/F2 proteins were identified in the same amino acid position (aa 108) as F proteins in LATC06, L13, RBT1, Kabete O, and RBOK strains. There are three predicted N-glycosylation sites of H proteins in LA (Japan) and LATC06 strains. The six epitopes of H protein in the LA (Japan) strain that elicit immunodominant humoral responses are also found in the LATC06 strain.

Specific detection of Rinderpest virus by real-time reverse transcription-PCR in preclinical and clinical samples from experimentally infected cattle.

A highly sensitive detection test for Rinderpest virus (RPV), based on a real-time reverse transcription-PCR (rRT-PCR)system, was developed. Five different RPV genomic targets were examined, and one was selected and optimized to detect viral RNA in infected tissue culture fluid with a level of detection ranging from 0.59 to 87.5 50% tissue culture infectious doses (TCID(50)) per reaction depending on the viral isolate. The strain sensitivity of the test was validated on 16 RPV strains belonging to all three phylogenetic branches described for RPV. No cross-reactivity was detected with closely related peste des petit ruminants or with symptomatically similar viruses, including all seven serotypes of foot-and-mouth disease virus, two serotypes of vesicular stomatitis virus, bluetongue virus, and bovine herpes virus type 2. In samples from experimentally infected cattle, our real-time RT-PCR test was significantly more sensitive than the gold standard test of virus isolation, allowing the detection of the disease 2 to 4 days prior to the appearance of clinical signs. The comparison of clinical samples with putative diagnostic value from live animals showed that conjunctival swabs and blood buffy coat were the samples of choice for epidemiological surveillance, while lymph nodes performed the best as postmortem specimens. This portable and rapid real-time RT-PCR has the capability of the preclinical detection of RPV and provides differential diagnosis from look-alike diseases of cattle. As RPV is declared globally eradicated, this test provides an important rapid virus detection tool that does not require the use of infectious virus and allows the processing of a large number of samples.

Rinderpest virus expressing enhanced green fluorescent protein as a separate transcription unit retains pathogenicity for cattle.

A full-length DNA clone of a virulent strain of rinderpest virus was constructed with the gene for the enhanced green fluorescent protein (eGFP) inserted as a separate transcription unit between the P and M genes. Rescue of the virus from the modified clone using reverse genetics generated a virus that grew to the same levels as the virus rescued from the unmodified DNA clone in cell culture. The recombinant virus expressed eGFP to a high level and was used to follow virus replication in real-time using live-cell imaging. Cattle infected with both the recombinant wild-type virus and the recombinant eGFP expressing virus developed clinical disease similar to that of the wild-type natural virus isolate. Detection of virus in circulating peripheral blood leukocytes was equivalent to that of the animals infected with the wild-type virus. The high level of expression of soluble eGFP by this virus allowed us to detect viral replication in infected animals by confocal microscopy. Imaging vibrating microtome sections by confocal microscopy provided good preservation of tissue and cellular architecture as well as revealing the sites of replication of the virus in different tissues of infected animals.

The rinderpest virus non-structural C protein blocks the induction of type 1 interferon.

The innate immune response, in particular the production of type 1 interferons, is an essential part of the mammalian host response to viral infection. We have previously shown that rinderpest virus, a morbillivirus closely related to the human pathogen measles virus, blocks the actions of type 1 and type 2 interferons. We show here that this virus can also block the induction of type 1 interferon. The viral non-structural C protein appears to be the active agent, since expressing this protein in cells makes them resistant to activation of the interferon-beta promoter while recombinant virus that does not express the C protein activates this promoter much more than virus expressing the C protein. In addition, differences in activation of the interferon-beta promoter by different strains of rinderpest virus are reflected in differing abilities of their respective C proteins to block activation of the promoter by dsRNA. The C protein blocks the activation of this promoter induced by either cytoplasmic dsRNA or by Newcastle disease virus (NDV) infection, as well as activation induced by overexpression of several elements of the signalling pathway, including mda-5, RIG-I and IRF-3. The RPV C protein also blocks transcription from promoters responsive individually to the three transcription factors that make up the interferon-beta promoter enhanceosome, although it does not appear to block the activation of IRF-3.