History of Veterinary Immunology in New Zealand.

Knowledge gained from veterinary immunology has played an important role in the control of microbial and parasitic diseases in New Zealand through the development and use of vaccines and diagnostic tests. In this article celebrating the 100th anniversary of the Journal, I follow the development of important discoveries in veterinary immunology which have led to major advances in the control of animal diseases.

subsp. antigens induce cellular immune responses in cattle without causing reactivity to tuberculin in the tuberculosis skin test.

subspecies (MAP) causes chronic progressive granulomatous enteritis leading to diarrhea, weight-loss, and eventual death in ruminants. Commercially available vaccine provides only partial protection against MAP infection and can interfere with the use of current diagnostic tests for bovine tuberculosis in cattle. Here, we characterized immune responses in calves to vaccines containing four truncated MAP antigens as a fusion (Ag85A-SOD-Ag85B-74F), either displayed on protein particles, or expressed as a soluble recombinant MAP (rMAP) fusion protein as well as to commercially available Silirum vaccine.

Test performance data demonstrates utility of a cattle DIVA skin test reagent (DST-F) compatible with BCG vaccination.

Bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis (M. bovis), is the lead candidate vaccine for control of bovine tuberculosis (TB) in cattle. However, BCG vaccination sensitises cattle to bovine tuberculin, thus compromising the use of the current bovine TB surveillance tests.

Self-assembled particulate vaccine elicits strong immune responses and reduces Mycobacterium avium subsp. paratuberculosis infection in mice.

Mycobacterium avium subspecies paratuberculosis (MAP) causes chronic progressive granulomatous enteritis leading to diarrhoea, weight loss, and eventual death in ruminants. Commercially available vaccines provide only partial protection against MAP infection and can compromise the use of bovine tuberculosis diagnostic tests. Here, we report the development of a protein-particle-based vaccine containing MAP antigens Ag85A-SOD-Ag85B-74F as a fusion ('MAP fusion protein particle').

BCG vaccination for bovine tuberculosis; conclusions from the Jerusalem One Health workshop.

The global burden of bovine tuberculosis (bTB) remains poorly characterized, with spill-over impacts on multiple species. The "One Health" concept is especially relevant given the bidirectional risk of cattle infecting humans with Mycobacterium bovis and humans infecting cattle with Mycobacterium tuberculosis. "Test and cull" is the traditional bTB control method, but the strategy may not be economically feasible or culturally acceptable where cattle are highly prized or their killing is a religious taboo; it is also less effective when there are wildlife reservoirs of infection.

Efficacy and Safety of BCG Vaccine for Control of Tuberculosis in Domestic Livestock and Wildlife.

Bovine tuberculosis (TB) continues to be an intractable problem in many countries, particularly where "test and slaughter" policies cannot be implemented or where wildlife reservoirs of infection serve as a recurrent source of infection for domestic livestock. Alternative control measures are urgently required and vaccination is a promising option. Although the bacille Calmette-Guérin (BCG) vaccine has been used in humans for nearly a century, its use in animals has been limited, principally as protection against TB has been incomplete and vaccination may result in animals reacting in the tuberculin skin test.

Low-dose BCG vaccination protects free-ranging cattle against naturally-acquired bovine tuberculosis.

Vaccination of cattle with Mycobacterium bovis BCG has been shown to protect against infection with virulent strains of M. bovis, and against resultant bovine tuberculosis (TB). Here we report on a large-scale trial in New Zealand where free-ranging cattle were vaccinated with 3 x 10 BCG via injection, a lower dose than any previously trialed in cattle against exposure to a natural force of M.

Detection of microRNA in cattle serum and their potential use to diagnose severity of Johne's disease.

Mycobacterium avium subspecies paratuberculosis (MAP) causes Johne's disease in ruminants, which is characterized by chronic progressive granulomatous enteritis. The infection leads to wasting and weight loss in the animals and eventually death, causing considerable production losses to the agricultural industry worldwide. Currently available ELISA- and PCR-based diagnostic tests have limited sensitivity and specificity during early MAP infection in cattle, suggesting that there is an urgent demand for alternative diagnostic tests.

Efficacy of oral BCG vaccination in protecting free-ranging cattle from natural infection by Mycobacterium bovis.

Vaccination of cattle against bovine tuberculosis could be a valuable control strategy, particularly in countries faced with intractable ongoing infection from a disease reservoir in wildlife. A field vaccination trial was undertaken in New Zealand. The trial included 1286 effectively free-ranging cattle stocked at low densities in a remote 7600ha area, with 55% of them vaccinated using Mycobacterium bovis BCG (Danish strain 1311).

Immunological properties and protective efficacy of a single mycobacterial antigen displayed on polyhydroxybutyrate beads.

In 2015, there were an estimated 10.4 million new tuberculosis (TB) cases and 1.4 million deaths worldwide.

Tuberculin Skin Testing Boosts Interferon Gamma Responses to DIVA Reagents in Mycobacterium bovis-Infected Cattle.

BCG vaccination sensitizes cattle to bovine tuberculin, which compromises the use of the current bovine tuberculosis (TB) surveillance tests. Although the performance of a blood test (that utilizes antigens expressed by but not by BCG) capable of discriminating infected from vaccinated animals (DIVA interferon gamma test [DIT]) has been evaluated in naturally infected TB field reactors, there is a need to perform similar analysis in a BCG-vaccinated -infected population. Furthermore, we explored different scenarios under which a DIT may be implemented alongside BCG vaccination: (i) serial testing to resolve potential false-positive skin test results or (ii) a standalone test to replace the single intradermal comparative cervical tuberculin (SICCT) skin test.

Factors affecting the gamma interferon test in the detection of bovine tuberculosis in cattle.

The gamma interferon (IFN-γ) test has been used for many years as an ancillary test in the detection of bovine tuberculosis. We investigated the effect of skin testing and the length of time between blood collection and processing on the performance of the IFN-γ test. A series of blood samples were taken from groups of experimentally infected cattle ( n = 10), naturally infected ( n = 11), and uninfected animals ( n = 12) that were examined with a caudal fold skin test.

Engineering Mycobacteria for the Production of Self-Assembling Biopolyesters Displaying Mycobacterial Antigens for Use as a Tuberculosis Vaccine.

Unlabelled: Tuberculosis (TB) is a disease caused by or and still remains one of the world's biggest global health burdens. Recently, engineered polyhydroxyalkanoate (PHA) biobeads that were produced in both and and displayed mycobacterial antigens were found to induce significant cell-mediated immune responses in mice. We observed that such PHA beads contained host cell proteins as impurities, which we hypothesized to have the potential to induce immunity.

Field Trial of an Aerially-Distributed Tuberculosis Vaccine in a Low-Density Wildlife Population of Brushtail Possums (Trichosurus vulpecula).

Oral-delivery Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine in a lipid matrix has been shown to confer protection against M. bovis infection and reduce the severity of tuberculosis (TB) when fed to brushtail possums (Trichosurus vulpecula), the major wildlife vector of bovine TB in New Zealand. Here we demonstrate the feasibility of aerial delivery of this live vaccine in bait form to an M.

Experimental infection of New Zealand Merino sheep with a suspension of Mycobacterium avium subspecies paratuberculosis (Map) strain Telford: Kinetics of the immune response, histopathology and Map culture.

A long-term study was undertaken to monitor immune responses, faecal cultures and clinical disease in sheep experimentally infected with Mycobacterium avium subspecies paratuberculosis (Map) strain Telford. New Zealand Merino lambs (N=56) were challenged with three oral doses of Map suspension. The lambs were weighed and faecal and blood samples obtained at different time-points.

Experimental Infection Models of Tuberculosis in Domestic Livestock.

In this article we present experimental Mycobacterium bovis infection models in domestic livestock species and how these models were applied to vaccine development, biomarker discovery, and the definition of specific antigens for the differential diagnosis of infected and vaccinated animals. In particular, we highlight synergies between human and bovine tuberculosis (TB) research approaches and data and propose that the application of bovine TB models could make a valuable contribution to human TB vaccine research and that close alignment of both research programs in a one health philosophy will lead to mutual and substantial benefits.

Sex difference in the survival rate of wild brushtail possums (Trichosurus vulpecula) experimentally challenged with bovine tuberculosis.

The main wildlife reservoir of bovine tuberculosis (TB) in New Zealand is the introduced brushtail possum (Trichosurus vulpecula), with spillover of infection from possums to livestock being regarded as the largest barrier to eradicating TB from the country. Past studies have experimentally challenged possums with Mycobacterium bovis (the causative agent of TB) to quantify infection parameters. However, the challenge models used are invariably non-representative of natural infection due to their resulting in much faster rates, and different clinical patterns of disease progression.

Vaccination of Sheep with a Methanogen Protein Provides Insight into Levels of Antibody in Saliva Needed to Target Ruminal Methanogens.

Methane is produced in the rumen of ruminant livestock by methanogens and is a major contributor to agricultural greenhouse gases. Vaccination against ruminal methanogens could reduce methane emissions by inducing antibodies in saliva which enter the rumen and impair ability of methanogens to produce methane. Presently, it is not known if vaccination can induce sufficient amounts of antibody in the saliva to target methanogen populations in the rumen and little is known about how long antibody in the rumen remains active.

Vaccination of cattle with a high dose of BCG vaccine 3 weeks after experimental infection with Mycobacterium bovis increased the inflammatory response, but not tuberculous pathology.

A study was undertaken to determine whether BCG vaccination of cattle post-challenge could have an effect on a very early Mycobacterium bovis infection. Three groups of calves (n = 12/group) were challenged endobronchially with M. bovis and slaughtered 13 weeks later to examine for tuberculous lesions.

The effectiveness of parallel gamma-interferon testing in New Zealand's bovine tuberculosis eradication programme.

In bovine tuberculosis (bTB) eradication programmes, especially where prevalence is low, sensitivity of testing in infected herds must be maximised to reduce the possibility of recrudescence of prior infection and the risk to other herds via animal movement. The gamma-interferon (γ-IFN) assay applied in parallel with intradermal tuberculin testing has been shown to increase test sensitivity. The aim of this work was to substantiate this effect in the field.

Development of immune-diagnostic reagents to diagnose bovine tuberculosis in cattle.

Bovine tuberculosis remains a major economic and animal welfare concern worldwide. As part of control strategies, cattle vaccination is being considered. This approach, used alongside conventional control policies, also requires the development of vaccine compatible diagnostic assays to distinguish infected from vaccinated animals (DIVA).

Bovine Tuberculosis in Cattle: Vaccines, DIVA Tests, and Host Biomarker Discovery.

Bovine tuberculosis remains a major economic and animal welfare concern worldwide. Cattle vaccination is being considered as part of control strategies. This approach, used alongside conventional control policies, also requires the development of vaccine-compatible diagnostic assays to distinguish vaccinated from infected animals (DIVA).

Display of Antigens on Polyester Inclusions Lowers the Antigen Concentration Required for a Bovine Tuberculosis Skin Test.

The tuberculin skin test is the primary screening test for the diagnosis of bovine tuberculosis (TB), and use of this test has been very valuable in the control of this disease in many countries. However, the test lacks specificity when cattle have been exposed to environmental mycobacteria or vaccinated with Mycobacterium bovis bacille Calmette-Guérin (BCG). Recent studies showed that the use of three or four recombinant mycobacterial proteins, including 6-kDa early secretory antigenic target (ESAT6), 10-kDa culture filtrate protein (CFP10), Rv3615c, and Rv3020c, or a peptide cocktail derived from those proteins, in the skin test greatly enhanced test specificity, with minimal loss of test sensitivity.