A Stochastic Simulation Model for the Efficacy of Vaccination Against Mycobacterium avium subsp. paratuberculosis in Dairy Sheep and Goats

Abstract. We assessed the benefits of vaccination against Mycobacterium avium subsp. paratuberculosis (MAP) on the average daily milk yield (DMY) of sheep and goat flocks. A stochastic simulation model was used to estimate the DMY pre and post vaccination of the flock replacements. The average DMY increased steadily for the first ten years post vaccination and then reached a plateau. Medians for the DMY were significantly higher post vaccination. The expected difference between the prevalence of MAP infection between and after the initiation of the vaccination program was the most influential factor for the DMY benefits. Vaccination of replacements in a MAP infected flock is expected to improve the overall milk productivity in the long term

A rational framework for evaluating the next generation of vaccines against Mycobacterium avium subspecies paratuberculosis

Since the early 1980s, several investigations have focused on developing a vaccine against Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of Johne\u27s disease in cattle and sheep. These studies used whole-cell inactived vaccines that have proven useful in limiting disease progression, but have not prevented infection. In contrast, modified live vaccines that invoke a Th1 type immune response, may improve protection against infection. Spurred by recent advances in the ability to create defined knockouts in MAP, several independent laboratories have developed modified live vaccine candidates by transcriptional mutation of virulence and metablolic genes in MAP. In order to accelerate the process of identification and comparative elvaluation of he most promising modified live MAP vaccine candidates, members of a multi-institutional USDA- funded research consortium, the Johne\u27s disease integrated program (JDIP), met to established a standardized testing platform using agreed upon protocols. A total of 22 candidates vaccine strains developed in five independent laboratories in the United States and New Zealand voluntarily entered into a double blind gated trial pipeline. In Phase I, the survival characteristics of each candidate were determined in bovine macrophages. Attenuated strains moved to Phase II, where tissue colonization of C57/BL6 mice were evaluated in a challenge model. In Phase III, five promising candidates from Phase I and II were evaluated for their ability to reduce fecal shedding, tissue colonization and pathology in a baby goat challenge model. Formation of a multi-institutional consortium for vaccine strain evaluation has revealed insights for the implementation of vaccine trials for Johne\u27s disease and other animals pathogens. We conclude by suggesting the best way forward based on this 3-phase trial experience and challenge the rationale for use of a macrophage-to-mouse-to native host pipeline for MAP vaccine development

MLA OJD Harvest Year Conference December 8-9, 2005.

Papers from the MLA 2005 Harvest Year conference program, including research on national and international perspectives of OJD; diagnosis; vaccination; public health and national programs; epidemiology; and economics.Meat and Livestock Australia Ltd Pfizer Animal Healt

Assessment of listing and categorisation of animal diseases within the framework of the Animal Health Law (Regulation (EU) No 2016/429): paratuberculosis

Non peer reviewe

Development of computer models to describe the epidemiology of Johne's disease in sheep.

The pathogenesis, epidemiology and options for control of Johne's disease in sheep were reviewed and mathematical models developed to simulate the spread of Johne’s disease within infected flocks, and between flocks on a regional basis. The models (the OJD Flock Model and the OJD Regional Model) also allow the evaluation and comparison of various control options at both flock and regional levels. Adequate data is still unavailable to allow accurate estimates of the true values for many of the models' parameters. However, as more precise estimates of the values of key parameters become available, the models will allow a rapid assessment of the likely impact of these values on our understanding of the disease

New perspectives on bovine tuberculosis diagnostics and control based on experimental infections.

200 p.La tuberculosis bovina continúa siendo a día de hoy una de las enfermedades infecciosas que mayores pérdidas económicas ocasiona al sector ganadero. El principal patógeno causante de esta enfermedad es Mycobacterium bovis (M. bovis). Aunque el ganado vacuno se encuentra sometido a campañas de erradicación existen otros animales de producción y silvestres afectados por la infección que pueden contribuir al mantenimiento de la misma ya que se encuentran exentos de seguimientos rutinarios. Los programas oficiales de erradicación de la tuberculosis en el ganado vacuno se basan en estrategias intensivas de detección y eliminación. Sin embargo, las limitaciones de los métodos de diagnóstico in vivo, en parte debido al complejo desarrollo de la enfermedad y a las reacciones cruzadas con otras micobacterias, junto con la ya mencionada existencia de reservorios, comprometen el éxito de las campañas de saneamiento bovino frente a la tuberculosis.El objetivo principal de esta tesis ha sido contribuir a mejorar el área de conocimiento de dos aspectos fundamentales de la tuberculosis bovina: el diagnóstico y la patogénesis. La tesis está compuesta por tres artículos de investigación publicados. Los dos primeros estudios se centraron en la relación existente entre M. bovis y Mycobacterium avium subsp. paratuberculosis (Map), agente responsable de la paratuberculosis. Tanto Map como las vacunas usadas frente a paratuberculosis pueden interferir con las técnicas diagnósticas frente a tuberculosis, lo que ha llevado a no permitir la vacunación frente a Map en ganado vacuno. En el tercer artículo se evaluaron las diferencias en el desarrollo de la infección con M. bovis en función de la ruta de entrada. Las conclusiones alcanzadas fueron las siguientes: 1. La interferencia ocasionada por la vacuna frente a paratuberculosis con las técnicas oficiales empleadas en el diagnóstico de la tuberculosis bovina puede evitarse por completo si se establecen nuevas estrategias de análisis como el uso de antígenos específicos o de interpretación, como nuevos criterios de diagnóstico para la intradermorreacción. 2. La vacunación frente a paratuberculosis puede conferir cierto grado de protección heteróloga frente a M. bovis, ya que se observó una disminución del nivel de gravedad de las lesiones así como de la carga bacteriana. 3. El desarrollo de una respuesta inmunitaria celular totalmente activa capaz de producir niveles detectables de IFN-¿ requiere de un período de tiempo superior tras una infección oral en comparación con una infección por vía aerógena. 4. La localización de las lesiones tuberculosas así como el tiempo requerido para el desarrollo de las mismas tras una infección con M. bovis varía en función de la vía de transmisión.Neiker Tecnali

Epidemiology of ovine paratuberculosis in New Zealand : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University, New Zealand

The overall goal of this PhD project was to better understand the general epidemiology of ovine paratuberculosis (PTb) and the specific molecular characteristics of the causing organism Mycobacterium avium subspecies paratuberculosis in New Zealand. To begin with, current control measures for clinical PTb in New Zealand’s major pastoral livestock species (dairy cattle, beef cattle, sheep, deer) were reviewed. Infection with Map is common in all these species and control is voluntary for all livestock industries. Control measures aim to reduce the incidence rate of clinical PTb rather than to eradicate Map infection. Dairy and deer industries have developed resources describing best-practice management options that assist farmers and veterinarians to advise their clients about specific control plans. There is no national control programme for sheep and beef cattle. However, unlike for cattle and deer, the use of a commercial vaccine is licensed for sheep. Evidence in this thesis suggests that vaccination may be a cost effective option for flocks that experience a high incidence of clinical disease. For deer, there is a national abattoir surveillance programme that aims to alert farmers of unusually high rates of PTb-like lesions in deer at slaughter. Evaluations of the biological and economic effectiveness of voluntary control still remains to be undertaken for all industries. Work in this thesis estimated the on-farm economic cost of clinical PTb in sheep (ovine Johne’s disease, OJD) in New Zealand. It was based on data about the incidence of clinical PTb and overall mortality from 20 OJD-affected farms. The benefit-cost ratio of vaccination was estimated. Farms were categorized as either fine-wool breed (Merino, Half-bred, Corriedale) or other breeds and calculations were stratified for these two farm categories. The estimated mortality due to OJD was 2.7 times as high in fine-wool as in other breeds with large variation between farms. A stochastic simulation for a hypothetical flock with 2,000 breeding ewes resulted in an average annual cost of OJD-mortality of NZ $13,100 in fine-wool and NZ$4,300 in other breeds. Vaccinating replacement lambs against OJD would be cost-effective in most flocks when the pre-vaccination annual OJD ewe mortality was >1%. Accurate on-farm observation of OJD to establish incidence would help farmers to make better decisions about vaccination. Frozen-stored faecal and serum samples of individual sheep with no signs of clinical disease from 45 commercial flocks from a 2013 study that determined pooled faecal culture (PFC) status were used to determine faecal Map shedding and antibody in serum. A total of 878 faecal samples were tested with direct faecal real-time quantitative PCR (qPCR) to determine Map shedding prevalence and abundance in individual animals. In addition, the qPCR results were compared with Map antibody ELISA results from 837 corresponding sera to correlate the observed shedding prevalence with sero-prevalence. Overall, 13.1% of faecal samples and 5.8% of serum samples tested positive. The median intra-flock prevalence (IFP) of Map shedding in the qPCR positive flocks was 13.5% with a range of 5–95%. The median IFP of Map ELISA antibody positive flocks was 10% with a range of 5–20%. ELISA results and the DNA concentration in qPCR positive samples were positively correlated. Nevertheless, ELISA was a poor predictor of individual shedding. A more robust assessment of the shedding status of flocks can be achieved by using a combination of qPCR and ELISA of individual animals rather than a single PFC of 20 randomly selected sheep per flock, as was used in the 2013 survey. Type S1 Map isolates from New Zealand and the Australian Telford strain were char- acterized based on single nucleotide variant (SNV) analysis of whole genome sequence data (WGS). A Type S1 genome was completely sequenced and closed for using as a reference for the SNV analysis. Besides defining the genetic relationship between Map isolates from New Zealand, Australia and Europe several phenotypic variables used as surrogates for the severity of PTb in individual hosts were investigated. The New Zealand and Australian isolates formed a closely related group. They were distinctly different from the Type S isolates from countries in Europe. Within New Zealand, Map genotypes and region of sheep farm locations were significantly associated (p <0.05). There were no significant associations between genotype and surrogates for severity, observed in the animals which the genotypes were isolated from, such as histopathological scores of intestinal lesions, host serology or the gross-pathological diagnosis by veterinarians at necropsy. These results suggested that the phenotypic variation of PTb may depend on factors other than Map-genotype in Type S strain. Further studies are required to sub-stantiate a hypothesis about varying virulence factors of the Map genome in New Zealand sheep. In summary, PTb control in New Zealand is voluntary in all major ruminant livestock industries including sheep. In clinically affected commercial sheep farms, estimated mortality due to OJD was 2.7 times as high in fine-wool as in other breeds, but large variations were observed between farms. PTb vaccination in commercial sheep flocks may be cost effective if annual incidence of OJD attributable ewe mortality is >1%. In non-clinical commercial flocks, the median IFP of Map shedding and Map ELISA antibody positive prevalence was 13.5% and 10% respectively. Approximately 1% ewes in qPCR positive flocks were supershedders. Based on analysis of WGS data, Type S Map genotypes from New Zealand sheep were similar across the country and not affected by the type of breed or disease outcome in hosts