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.

The major application of veterinary immunology in New Zealand has been in the development and implementation of vaccines and diagnostic tests for the control or eradication of microbial and parasitic diseases.For vaccine development, immunological knowledge has become increasingly important to determine the type of immune response required for protection against specific diseases, selection of an effective antigenic formulation, appropriate adjuvant and development of assays to assess efficacy of the vaccines.Over the past 80 years in New Zealand, numerous vaccines have been developed and commercially produced in the country to markedly reduce the prevalence of diseases that had previously caused major economic losses in cattle, sheep and deer industries.In addition, the application of immunological diagnostic tests has resulted in the eradication or control of a number of these animal diseases.
The development and commercialization of improved clostridial diseases were initiated in the 1940s by Malcolm Buddle at Wallaceville Animal Research Centre (WARC) 1 (Figure 1).Before this time, deaths from blackleg, pulpy kidney and malignant edema were common in sheep and cattle and the new vaccines produced at WARC against Clostridium chauvoei, septicum, welchii C and D were shown to be protective against these diseases.The vaccines were initially provided free to farmers, but as demand increased government officials decided that the vaccines should be manufactured by commercial companies.The vaccines brought in from Australia did not prove to be as effective against the clostridial strains present in New Zealand, which led to the establishment of New Zealand's first commercial vaccine company, Tasman Vaccine Laboratory.This company has become a global vaccine company currently owned by MSD, producing a wide range of veterinary vaccines, many of which have been developed in New Zealand.
Bovine brucellosis caused by Brucella abortus was a common cause of abortion in cattle as well as causing undulant fever in humans and in 1966, a slaughterhouse survey in New Zealand identified 15% of cattle to be infected.Vaccination of female calves with "strain 19" B. abortus vaccine started in the mid-1960s, leading to a marked reduction in the disease.This was followed up in 1969 with a program led by Wally Te Punga at WARC to eradicate the disease based on the use of complement fixation test serological test.This test was cumbersome, with a trained technician performing only 90-100 tests a day, necessitating the development of autoanalyzers to perform this test for the large-scale analysis of blood samples. 2 Testing reached a peak in 1975 when 2.6 million samples were processed.In 1988, the last isolate of B. abortus was recovered from cattle, and in 1991, New Zealand was declared free of bovine brucellosis and in 1996, the Office International des Epizooties (OIE) accepted New Zealand's diseasefree status.
Leptospirosis was shown to be an important problem in cattle and pigs, and research at Massey University by Roger Marshall and David Blackmore led to the development of a bivalent vaccine which was introduced for cattle in 1979.The use of the vaccine in dairy cattle led to a dramatic decrease in the incidence of the disease in these species as well as in farmers and abattoir workers.Improved diagnostics based on microagglutination tests were introduced through the 1980s. 3artin Skerman from WARC, in collaboration with the New Zealand vaccine company, developed a vaccine to protect against foot rot in sheep, based on incorporation of pili from 10 strains of Dichelobacter nodosus. 4Two cestodes that caused problems in New Zealand were Taenia ovis (sheep measles) and Echinococcus granulosus (true hydatids).David Heath from WARC and collaborators produced an effective vaccine against T. ovis based on the identification of an immunogenic protein from oncospheres, with the vaccine incorporating the recombinant oncosphere protein produced in Escherichia coli.This work was published in Nature in 1989 and was reported to be the first effective recombinant protein vaccine to protect against a parasitic disease. 5A similar technology was used to produce a recombinant protein vaccine against E. granulosus to protect sheep, cattle and yaks and the vaccine has been trialed in China and Argentina.
In 1992, all the government research centers were reorganized into nine Crown research organizations and research focused on pastoral farming was combined into an organization called AgResearch Ltd.Vaccines against toxoplasma abortion in sheep, campylobacter abortion in sheep, yersiniosis in deer and a twinning vaccine for sheep were developed principally by AgResearch staff.These vaccines were manufactured and marketed by a subsidiary of AgResearch in the period 1993-2005, after which they were sold to MSD.For the toxoplasma vaccine, Murray Wilkins and Elaine O'Connell passaged a strain to Toxoplasma gondii two times a week intraperitoneally in mice for a total of 3000 passages over 20 years.Over this time, the strain lost its capacity to form oocysts in cats, and vaccination of ewes with the resulting live tachyzoites protected ewes from toxoplasma abortion. 6By contrast, killed tachyzoites induced no protection, and antibody titers did not correlate with protection.Methods were developed for freezing the tachyzoites and in the early 1980s, the propagation of the tachyzoites was adapted to Vero cells.Although the vaccine shelf life was initially very short, 14 days, it was gradually increased.The vaccine was made-to-order and shipped within 24 hours to anywhere in New Zealand.through a collaboration involving Colin Mackintosh and Bryce Buddle from AgResearch and Frank Griffin from the University of Otago.The fourth vaccine to be developed by AgResearch and commercialized through their subsidiary company was a twinning vaccine for sheep based on research led by Ken McNatty.The principle of the vaccine was immunization with a steroid androstenedione-protein complex which prevented androstenedione from being metabolized to estradiol and temporarily blocked the release of eggs from ovaries.More eggs matured and when antibody levels fell, these extra eggs were released, potentially increasing the number of lambs born.To be effective, the vaccine needed to induce a low antibody response, with a high antibody response inducing temporary infertility, necessitating a requirement for a specific antigenic dose and appropriate adjuvant. 7Use of the vaccine increased lambing percentage by an average of 20%.
The prevalence of bovine tuberculosis in New Zealand has dramatically decreased in the past 50 years and the use of improved immunological diagnostic tests has played an important role in the control of this disease as well as provided farmers with confidence in the control program.The intradermal skin test, which was developed more than 100 years ago by Calmette and Gu erin in France, has been the principal test to detect infected cattle and farmed deer.However, since the 1990s, the tuberculosis eradication program in cattle has used a complementary test based on the gamma-interferon (c-IFN) test, developed by Paul Wood's group at the Commonwealth Scientific and Industrial Research Organisation (CSIRO) in Australia and more recently, using a refinement of the c-IFN test with the inclusion of antigens that are specific for Mycobacterium bovis to differentiate infections from other mycobacteria. 8 deer, the skin testing has been supplemented with complementary tests, including a combination of lymphocyte transformation and serological tests as described by Frank Griffin. 9 Vaccine studies at AgResearch (led by Geoffery de Lisle, Bryce Buddle and Desmond Collins) showed that Bacillus Calmette-Gu erin (BCG) vaccine can induce a level of protection against challenge with M. bovis in cattle and brushtail possums, the wildlife reservoir of infection.Further improvements in protection were shown using combinations of BCG vaccine and M. bovis proteins or DNA for cattle, or the use of novel genetically attenuated M. bovis for possums. 10An oral bait formulation of BCG produced by Frank Aldwell (Otago University) was shown to significantly induce protection against M. bovis in possums in field trials. 11BCG vaccine was also shown to induce a level of protection against tuberculosis in deer (Frank Griffin and Colin Mackintosh).
Immunological profiles of deer challenged with Johne's disease have been used to identify genetic resistance to this disease in a work led by Frank Griffin and Colin Mackintosh. 12A method to identify ruminants resistant to gastrointestinal nematodes (GINs) has been developed by Richard Shaw, AgResearch, based on elevated levels of immunoglobulin A in saliva to CarLA, a glycan found on the surface of third-stage larvae of GIN. 13 The CARLA test is a good measure of the protective immune response to GIN The vaccine was administered as a single dose to ewes mated for the first time and by the mid-1990s, 5-6 million doses of vaccines were sold per year.The use of the vaccine in the first 12 years saved the New Zealand sheep industry NZ $140 million.Campylobacter fetus was another common cause of abortion in sheep and a killed multistrain campylobacter vaccine was developed against this disease by Geoffrey de Lisle at AgResearch.A three-strain C. fetus vaccine was launched in 2003 and a C. jejuni strain was added to the vaccine in 2005.Ewes in the first year of pregnancy received two doses of the vaccine, 4-6 weeks apart, before mating, followed by a yearly booster.A whole-cell microagglutination test was used for measuring antibody responses.Yersiniosis has been a major cause of death in young deer calves and a killed vaccine incorporating three strains of Yersinia pseudotuberculosis was developed and commercialized

Figure 1 .
Figure 1.Two of the main buildings at Wallaceville Animal Research Centre, Upper Hutt, New Zealand, where most of the immunological studies were undertaken.The photo was taken by AgResearch staff and forwarded to the Upper Hutt Public Library archive.
Proc Royal Soc B Bio Sci 2009; 276: 2987-2995.12. Mackintosh CG, Clark RG, Tolentino B, de Lisle GW, Liggett S, Griffin JFT.Immunological and pathological responses of red deer resistant or susceptible genotypes, to experimental challenge with Mycobacterium avium subsp.paratuberculosis.Vet Immunol Immunopathol 2011; 143: 131-142.13.Shaw RJ, Morris CA, Wheeler M. 2023 The Authors.Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. ª