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Item Design and engineering of self-assembling antigens towards particulate vaccines : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Microbiology at Massey University, Palmerston North, New Zealand(Massey University, 2019) Chen, ShuxiongNatural and synthetic self-assembling polymers and proteins could be bioengineered to display and/or encapsulate antigens to serve as innovative antigen carrier systems for the induction of desirable immunities. Polyhydroxyalkanoates (PHAs) are naturally occurring polyesters synthesized as cytoplasmic polyester inclusions (polyester particles) by various bacteria. The particles have been used as an antigen delivery platform by translationally fusing antigens to the particle surface-associated protein, PHA synthase. Furthermore, it has been found that protein inclusion bodies contain a large amount of correctly folded and biologically active proteins and could be engineered to perform as an antigen carrier system. Tuberculosis (TB) is a global health issue for both humans and animals. Inaccurate diagnosis and inefficacious vaccination make TB control problematic. The Mantoux tuberculin skin test gives false positive results if humans or animals are vaccinated with the Bacille Calmette-Guérin (BCG) strain or exposed to environmental mycobacteria. BCG cannot provide effective protection against TB. Subunit vaccines have great promise to protect against infectious diseases, but they are often weak immunogenically. A strategy to circumvent this problem is the use of self-assembly particulate vaccines, which could present multiple copies of antigens and serve as a depot for prolonged multivalent antigen display to induce enhanced immunogenicity. In this thesis, four specific TB diagnostic antigens — CFP10, Rv3615c, ESAT6, and Rv3020c — were displayed on polyester particles. The results showed that polyester particles displaying TB antigens specifically distinguished TB-infected from non-infected cattle. Antigen immunogenicity was dramatically enhanced after the display on polyester particles, which lowered the antigen concentration (0.1 to 3 μg dose/inoculum) required for skin tests. Mycobacterial vaccines H4 (Ag85B-TB10.4) or H28 (Ag85B-TB10.4-Rv2660c) were bioengineered to display H4/H28 on polyester particles and/or self-assemble H4/H28 into protein inclusion bodies. The results demonstrated that polyester particle-/protein inclusion body-based particulate TB vaccines increased overall immunogenicity by enhancing humoral (for example, IgG1 and IgG2c) and cellular (for example, IFNγ and IL17A) immune responses when compared to respective soluble antigens.Item Optimising the use of new data streams for making epidemiological inferences in veterinary epidemiology : a thesis presented in partial fulfilment of the requirements for the degree of PhD in Veterinary Epidemiology at Massey University, Manawatu, New Zealand(Massey University, 2018) Hidano, ArataMany ‘big data’ streams have recently become available in animal health disciplines. While these data may be able to provide valuable epidemiological information, researchers are at risk of making erroneous inferences if limitations in these data are overlooked. This thesis focused on understanding the better use of two data streams—livestock movement records and genetic sequence data. The first study analysed national dairy cattle movement data in New Zealand to explore whether regionalisation of the country based on bovine tuberculosis risk influenced trade decisions. The results suggested that the observed livestock movement patterns could be explained by the majority of, but not all, farmers avoiding purchasing cattle from high disease risk areas. The second study took an alternative approach—qualitative interviews—to understanding farmers’ livestock purchasing practices. This study suggested that farmers are not necessarily concerned with disease status of source farms and that it may be the reliance on stock agents to facilitate trade that creates the observed livestock movement patterns in New Zealand. The findings from this study also implied that various demographic and production characteristics of animals may influence farmers’ livestock selling practices, which were quantitatively verified in the third study analysing livestock movement data and animal production data. These studies not only showed that analyses based solely on ‘big data’ can be misleading but also provided useful information necessary to predict future livestock movement patterns. The final study evaluated the performance of various genetic sequence sampling strategies in making phylodynamic inferences. We showed that using all available genetic samples can be not only computationally expensive, but also may lead to erroneous inferences. The results also suggested that strategies for sampling genetic sequences for phylodynamic analyses may need to be tailored based on epidemiological characteristics of each epidemic.Item The population dynamics of bovine tuberculosis in possums : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Mathematics at Massey University(Massey University, 1991) Sleeman, MareeWith the recent outcry concerning the spread of Bovine Tuberculosis throughout the New Zealand Possum population, there is an increasing need to study some of the diverse modelling approaches to this problem. This thesis centres on modelling the epidemics of this disease using two and three-dimensional dynamical systems, which describe the change in the possum population and change in the number of individuals that are diseased. Introductory material is covered in Chapter One, which reports on the first, through to some of the most recent research completed in the area of disease epidemics. A review of the previous model of possum tuberculosis is also introduced. Chapter Two looks at the effects on the dynamics of the model of changing the recovery curve parameter, which measures the degree of recovery of possums following a control operation. Detailed steady-state analysis is carried out on the system and local stability determined. In Chapter Three, a three-dimensional model is investigated that allows for a latent period following infection of disease. Instead of a possum being able to spread the disease immediately after becoming infected itself, there is a latent time until the disease becomes contagious. An in-depth description is given as to how this model originates, then steady-state analysis is explored, and finally local stability of the steady-states is examined. Restricting the contact rate of an individual possum with the rest of the population is the model studied in Chapter Four. Rather than a possum being able to come in contact with the whole population in a set time, as was the situation in the previous models, the number of contacts is fixed at some realistic value for the given time period. Steady-state analysis is carried out for this new model, along with the local stability analysis. Chapter Five looks at the various models and how they relate to the model in Chapter Two. as this model is the base for the subsequent ones. Computer generated plots are examined in order to display the numerical differences between the models. A brief comparison is given between these and some other models in the literature, and concludes by discussing some of the advantages and disadvantages of the various models. Finally, Chapter Six discusses the need for implementing spatially distributed models in the future, to allow for patchiness within the population.Item An Australian abroad : the secret life of the brushtail possum (Trichosurus vulpecula) : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Veterinary Science at Massey University, Manawatu, New Zealand(Massey University, 2016) Richardson, Kyle StephenThe “superspreader” hypothesis relates disease transmission to social contacts and assumes transmission is driven by the frequency, type and distribution of contacts among infected and susceptible individuals. I investigated characteristics of brushtail possum (Trichosurus vulpecula) home ranges for six wild free-living subpopulations, (four grids were studied; all of them before possum depopulation and two of them after possum depopulation) constructing social networks relevant to bovine tuberculosis (TB) transmission before and after depopulation. I also experimentally infected possums with a novel strain of TB to monitor secondary case infections in relation to these contact and other factors, including population density and sex ratio. Before depopulation home range estimates showed adult males had larger home ranges than female and younger possums. Home range overlap and area of overlap differed between subpopulations, and possum sex and age; with adult males having more and larger overlaps with other possums. Possums were fitted with proximity-logging collars and contacts registered between April and October, 2012. The number of connections an individual has with others and the probability of the distribution of contacts it has within the population, or node degree and betweenness, also known as the shortest distance between individuals, were associated with sex, with males having higher values for each. Males also contacted more possums than females. Post-depopulation results showed an influx of male possums, higher population density, and smaller home range sizes than before depopulation. Possums post-depopulation also lacked an apparent ‘routine’ in contact networks, interacting with other possums haphazardly. The greater level of contact among adult males, than before depopulation, and their effects on recovering populations post-depopulation, was likely the cause of more TB infection in adults and males. This thesis provides empirical evidence that adult male possums have home range and contact network characteristics that are likely to enhance their involvement in the transmission and persistence of TB, relative to female and younger possums. Observations of experimentally infected individuals showed that infected males survived longer than females and that, as a consequence, those males potentially acted as a “supershedding” subgroup. I therefore provide evidence that adult male possums are the most important drivers of TB transmission and persistence of infection in populations, and could be targeted for control measures.Item Risk factors for detection of recurrent bovine tuberculosis in New Zealand cattle and deer herds 2005-2011 : a dissertation presented in partial fulfillment of the requirements for the degree of Master of Veterinary Studies (Epidemiology) at Massey University, Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Palmerston North, New Zealand(Massey University, 2014) Dawson, Kara LeeIn New Zealand, under the national bTB eradication strategy, bovine tuberculosis (bTB) has had a sustained decrease in prevalence since its peak in 1994 at 1700 infected herds. With the success of control measures, recurrence of infection in cattle and deer herds that have previously tested to a clear status is a problem that has recently become more apparent. Uncontrolled movement of cattle and deer from these herds pose a risk to the bTB eradication strategy. A retrospective cohort study was conducted to identify herd-level risk factors for bTB recurrence. Data were collected from 356 New Zealand cattle and deer herds that met the following criteria: (1) a culture positive case of bTB had been identified on or after 1 June 2006 (the index bTB episode), (2) the herd status had been cleared by testing that was completed by 1 November 2010, and (3) the clear status was not achieved by destocking. The outcome of interest for this study was defined as detection of a subsequent bTB episode before the end date of the study, 5 May 2011, by routine tuberculin testing or by slaughter surveillance. Herds were censored if no further bTB episode occurred by 5 May 2011. A Cox proportional hazards model was developed to quantify the magnitude of a series of herd-level risk factors on the daily hazard of bTB recurrence. Disease control area was included in the model as a fixed effect to account for confounding. There was a positive relationship between the daily hazard of recurrence and: (a) the number of bTB episodes in a herd prior to the first episode (HR [hazard ratio] 3.2 for two prior episodes, 95 % CI 1.2-8.5; HR 86.7 for five prior episodes, 95 % CI 13.8-580), (b) the presence of more than one bTB positive animal at the index bTB episode (HR 2.3: 95 % CI 1.2-4.3) and (c) the presence of one or more cleared test-positives at the final clearance test at the index episode. The proportional hazards assumption was violated for the latter variable so a time dependent covariate was introduced into the model to account for the variable effect of the presence of cleared test-positives at the final clearance test over time. The monthly hazard of recurrence during the first two years after clearance was significantly increased in herds with one or more test-positive animals at the final test (HR 2.8: 95 % CI 1.2-6.4), but this association was no longer significant more than two years after clearance (HR 1.5: 95 % CI 0.6-3.6). We conclude that the presence of unresolved infection in a herd is a contributor to further bTB episodes in the first two years after clearance. TBfree New Zealand is reviewing policies to increase the sensitivity of detecting residual infection before clearance and to intensify post clearance testing and movement tracking in herds with risk factors.Item The role of a wildlife reservoir in the epidemiology of bovine tuberculosis : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University(Massey University, 1994) Pfeiffer, D. U.The objective of this project was to study the epidemiology of bovine tuberculosis in the presence of a wildlife reservoir species. Cross-sectional and longitudinal studies of possum populations with endemic bovine tuberculosis infection were analysed. The results were used to develop a computer simulation model of the dynamics of bovine tuberculosis infection in possum populations. A case-control study of breakdowns to tuberculosis infection in cattle herds in the Central North Island of New Zealand was conducted to identify risk factors other than exposure to tuberculosis in local possum populations. The cross-sectional study was based on data gathered some years earlier in the Hauhungaroa Ranges from a number of traplines with a total length of 60km, hence it provided information about the epidemiology of possum tuberculosis on a large geographical scale with varying environmental conditions. The results from the study showed that disease occurrence was clustered in space with local prevalence reaching up to 20% while the overall prevalence was about 1.2%. The longitudinal study was conducted using an area of 21 hectare of mixed pasture and bush on a sheep/beef farm. The study showed that incidence and prevalence of tuberculosis infection in possum populations has distinct spatial and temporal patterns. Environmental conditions were a major factor in determining the temporal pattern. Spatial and temporal analysis of the occurrence of different strains of Mycobacterium bovis allowed inferences to be made about the importance of particular transmission paths. Survival of possums depended on environmental conditions and tuberculosis disease status. Adverse weather conditions increased mortality and the incidence of clinical disease in possums. On average clinically tuberculous possums survived for about 2 to 3 months from the onset of clinical disease. The simulation model uses a Monte-Carlo modelling approach and incorporates geographical features. Biological mechanisms which are considered important for population and infection dynamics were implemented in the model. These include mating, density-dependent and -independent mortality, pseudo-vertical transmission, transmission through spatial or temporal proximity, and transmission during mating contact. Each possum's movements and behaviour are simulated on a day-by-day basis. Simulations are conducted using a geography and possum population based on data from the longitudinal field study. For preliminary validation, model output was compared with field data from the longitudinal study. Sensitivity analyses and some initial simulation experiments were conducted to identify areas in the model structure which require the collection of additional field data. Use of the model for simulation of a possum population occupying a 400ha area in the Central North Island of New Zealand is demonstrated. The case-control study of breakdowns to tuberculosis infection in cattle herds showed that in the Waikato area of New Zealand exposure to tuberculosis infection in local possum populations was not the dominant cause of breakdowns when the study was conducted in 1989/90, at a time when tuberculous possums were first discovered in the region. Farmers who had breakdowns tended to follow cattle purchase and management practices which traditionally have been considered to put farms at risk of introducing tuberculosis. The results of the study indicate that there was a lack understanding among farmers about the epidemiology of tuberculosis.Item A genetic approach to identify Mycobacterium bovis exported protein antigens : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Molecular Biology, Massey University(Massey University, 1997) Borich, Suzanne MarieA novel approach, combining phoA-fusion technology with T cell screening of a recombinant cosmid library, was used to detect Mycobacterium bovis exported T cell antigens. An M. bovis BCG library of phoA-fusions was constructed in Escherichia coli and Mycobacterium smegmatis using the plasmid vector pJEM11. The M. bovis BCG DNA inserts from ten PhoA+ clones were partially sequenced and used to search databases for similarities to known genes. These revealed similarities to a family of genes coding for high temperature-requirement serine proteases and a Mycobacterium leprae putative exported lipoprotein gene (pel). The DNA inserts from PhoA+ clones were used to probe an M. bovis cosmid library expressed in M. smegmatis 10 identify cosmids containing the full-length genes coding for these exported proteins. Culture filtrates (CFs) prepared from selected M. smegmatis recombinants (cosmids) were assayed for their ability to induce proliferation and IFN-γ-production from peripheral blood mononuclear cells (PBMCs) taken from M. bovis BCG-immunised and non-immunised control cattle. Culture filtrates from two recombinant M. smegmatis (cosmids 44 and 56) induced significant IFN-γ-production and proliferation by PBMCs from immunised animals. An exported protein gene, identified using the phoA-fusion technology, was subcloned from cosmid 56 and its sequence determined and analysed. Database searches using the deduced amino acid sequence of this gene revealed similarities to an M. leprae putative exported lipoprotein (Pel) and a family of MalE maltose-binding proteins. The M. bovis pel gene was shown to be expressed by recombinant M. smegmatis. Preliminary evidence from this study indicates that the M. bovis Pel protein is recognised by antigen-specific lymphocytes from M. bovis BCG-immunised animals. The PBMCs taken from M. bovis challenged and M. bovis BCG vaccinated / challenged cattle also recognised CF from recombinant M. smegmatis expressing the pel gene in in vitro immunoassays. The combined strategy of using phoA-gene fusions and T cell screening of CFs from a recombinant M. bovis cosmid library proved a sensitive and rapid method for the detection of potential M. bovis T cell antigens.Item The use of habitat analysis in the control of wildlife tuberculosis in New Zealand : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University(Massey University, 1999) McKenzie, JoannaThe brushtail possum (Trichosurus vulpecula) acts as a wildlife reservoir of Mycobacterium bovis infection for farmed livestock and other wildlife species in areas covering an estimated 23 percent of New Zealand. This reservoir of infection is severely hampering efforts to eradicate TB from farmed animals in New Zealand. New strategies need to be developed that focus on identifying areas of residual TB infection in possums and eradicating them, while maintaining low broad-scale population levels in the most cost-effective way. This thesis comprise a number of studies that apply multivariate modelling techniques and spatial analytical procedures to evaluate spatial patterns of possum habitat and of TB occurrence in cattle herds, and hence to identify high-risk localities for possum-derived TB and target control strategies of varying intensity where each will be most cost-effective. An initial case-control study of 132 possum capture sites was used to identify habitat and topographic factors at the scale of the possum home range that were predictors of the probability of capturing tuberculous possums. Data on the following factors were collected from a 50 meter square area at each capture site: abundance of plant species and structural features of vegetation, the abundance and quality of available den sites, and topographic factors such as slope and aspect. Data were analysed using unconditional logistic regression modelling. Slope of the land and factors associated with the quality of dens were associated with the probability of capturing multiple TB possums. Slope of the land, height of trees, percent cover of vegetation in the height range 0.3 - 2 metres and percent of the ground covered in vascular vegetation were associated with the probability of capturing single TB possums. A subsequent case control study was conducted at the larger scale of farms to identify possum habitat, geographic and farm factors associated with the probability of tuberculous possums being present on a farm, using random effects logistic regression modelling. A geographic information system (GIS) was used to combine and analyse digital geographic data sets to produce variables for the statistical analysis. Geographic data used for the study comprised farm boundaries, rivers, slope, and vegetation coverage which was derived from satellite imagery. Fragstats, a habitat pattern analysis programme, was used to produce variables representing patterns of possum habitat on farms. Variables were included in the model to account for spatial autocorrelation patterns in the data and a variogram analysis was conducted on residuals to test for any significant spatial autocorrelation that was not accounted for in the model. Distance from the coastal forest, total area of the farm, area of pine forest, area of manuka/pasture and proportion of the farm covered with podocarp/broadleaved species were the significant variables in the final model. An automated classification procedure was used to generate a vegetation map from a SPOT3 multi-spectral satellite image for this study. The resulting raster map comprised 8 vegetation classes, including 3 tree classes, 4 scrub classes and a pasture class. This map had a high degree of spatial accuracy and more detailed vegetation classes than existing digital data available in New Zealand. However, some categories contained a heterogeneous range of plant species which limited the discriminatory power of models using this vegetation data. Spatial clustering of percent TB-positive years, five-year cumulative incidence and space-time clustering of annual cumulative incidence of TB in cattle were analysed for beef breeding farms in the area in which the farm-level case control study was conducted. Analyses used the spatial and space-time scan statistics which are available in SaTScan, a cluster analysis software package. Mapping of farms included in the resulting clusters enabled us to develop hypotheses on the association of different habitat patterns with the resulting disease patterns in cattle. This study also highlighted the value of these cluster analysis techniques as tools in surveillance for wildlife TB, by using farm-level patterns of TB as an indicator of the possible presence of wildlife TB. The final stage of the project described in this thesis was the development of EpiMAN-TB, a spatial decision support system for the management of wildlife-related TB in New Zealand. Development of this tool was undertaken to assist the application of the research results described in this thesis at the field level. The system combined a relational database, map display tools, spatial analysis tools, simple expert systems and simulation models of the spread of TB in possums at the scale of individual farms and administrative regions. The software comprises five modules set within a user-friendly interface. The modules are: possum TB hot spot prediction, farm TB risk prediction, evaluation of possum control programmes at the farm and the regional level, and an administration module.