General Considerations and Paratuberculosis Vaccination History

Vaccination has been the backbone of programmes for the only two infectious diseases that have been eradicated from the world: smallpox (WHO, 2018) and rinderpest (OIE, World Organisation for Animal Health, 2013).

Unfortunately, immunity conferred by mycobacterial vaccines is not 100% effective and lifelong as it is for these two diseases. This is either because individuals are already infected when first dosed, or because immunity is not strong enough to prevent infection. The result is that even for populations 100% covered, there is a small number of vaccinated individuals that become carriers, even though none of them progresses to clinical disease. On the positive side however, paratuberculosis is a slow infection (Sigurdsson, 1954) with low rates of both transmission and clinical disease progression. This means that slight increases in individual resistance and small reductions in bacterial shedding can contribute to reducing economic losses in the short term and in the longer term, clearing herds from the infectious agent.

Paratuberculosis was recognized as a clinical infectious disease right at the time when microbes were first being discovered and demonstrated as a cause of disease (Johne and Frothingham, 1895). With the quick success of Pasteur vaccination against rabies (Berche, 2012) and the perspectives opened by Bacillus Calmette-Guerin (BCG) tuberculosis vaccination (Nieuwenhuizen and Kaufmann, 2018) it was natural that the first choice for a control strategy against a disease similar to tuberculosis was the development of a

‘Corresponding author: rjuste@neiker.eus © CAB International 2020. Paratuberculosis: Organism, Disease, Control, 2nd Edition (eds M.A. Behr et al.)

vaccine. According to contemporary knowledge, French scientists (Vallee and Rinjard, 1926) developed a product for use in cattle that had an effect owing to both the mycobacterial cell components and the strong adjuvants (pumice powder and oil emulsion).

This vaccine was made available to veterinarians in France in the 1920s and was continued at least until the 1940s (Vallee et al., 1941). A similar vaccination strategy was soon adopted in the USA, where a vaccine was assayed with good results regarding mortality and pathology, but not when measuring Mycobacterium avium subsp. paratuberculosis (MAP) isolation (Hagan, 1935). No further studies on vaccination in cattle were reported until almost 25 years later, when a series of studies carried out in the UK (Doyle, 1960; Stuart, 1962, 1965) provided results considered highly satisfactory to the farmers (Doyle, 1964). By that time, studies on vaccination were going on in the National Animal Disease Center (NADC) (Larsen, 1950; Larsen et al., 1964; Merkal et al., 1965; Larsen et al., 1969, 1974, 1978) and later in the field (Hurley, 1983; Hurley and Ewing, 1983). Then there were reports from Denmark (Jorgensen, 1983, 1988), France (Hillion and Argente, 1987; Argente, 1992; Saint-Marc, 1992) and the Netherlands (Benedictus et al., 1988; Kalis et al., 1992, 1995, 2001, 2002; van Schaik et al., 1996; Kalis et al., 1999). By the late 1980s, even though test-and-cull programmes based on faecal culture were being abandoned, scientific reports on vaccination were becoming scarce.

The cattle experience set the ground for the use of vaccination when paratuberculosis appeared in an epidemic form in sheep in Iceland in the 1930s after the introduction of a few MAP- infected Karakul rams that were also carriers of the then unknown maedi-visna. While the new viral disease was eradicated in a few years by a culling strategy, paratuberculosis could not be brought under control until a vaccine was produced and vaccination was made compulsory (Sigurdsson and Tryggvadottir, 1949; Sigurdsson, 1960; Gunnarsson et al., 1984), as it remains until now. The Icelandic reports drew the attention of the Moredun Research Institute, which initiated a research programme on sheep paratuberculosis that generated important knowledge on pathogenesis and vaccination (Brotherston and Gilmour, 1961; Gilmour and Brotherston, 1962; Nisbet et al., 1962; Gilmour and Angus, 1973).

Vaccination was also adopted as a solution for paratuberculosis in goats in Norway (Saxegaard, 1984; Saxegaard and Fodstad, 1985). In Spain, paratuberculosis vaccination was implemented in the late 1970s as an official measure with both a French and a Spanish live vaccine freely issued to farmers until the late 1990s, where it was left at farmers' cost. During that period about 200,000 doses/ year were used according to the Ministry of Agriculture (Tejedor, 1993).

The 1990s and the first decade of the 21st century saw a few experiments in the search for new vaccines taking advantage of the new molecular technologies available. Then, Australia's change of control policy against paratuberculosis in sheep - from eradication by stamping out infected flocks to control by vaccination - started generating a large amount of literature on paratuberculosis in general and on its control by vaccination in particular (Windsor et al., 2002; Bush et al., 2006).

This information was reviewed in a metaanalysis in 2011, where it was shown that vaccination induced beneficial results in all species in almost any setting (Bastida and Juste, 2011), despite results that fail to reach 100% protection. Still, although the idea of using vaccination in small ruminants, deer and camelids seems to be well established, the cattle industry is reluctant to use it for two reasons: interference with bovine tuberculosis diagnosis and fears of delay in eliminating risks for food safety due to the presence of MAP in milk and other products. Even so, a recent review on paratuberculosis control throughout the world showed that vaccination was in place in about 32% of 48 countries (Whittington et al., 2019). Vaccine production has always been a reduced circle, with fabrication limited to a handful of laboratories, mostly from governments. In addition to the French vaccine, originally produced by Rhone-Merieux, Keldur central veterinary laboratory in Iceland and Weybridge central laboratory in the UK produced vaccine for national industry, as well as the national laboratories in Denmark and Norway.

In the USA, the vaccine was produced by Solvay, later absorbed by Boehringer- Ingelheim, while in Spain, there was Ovejero in the 19 80s, who produced a live vaccine that was later replaced by a killed one manufactured by CZVeterinaria (now CZVaccines). Currently, however, after discontinuation of commercial

Table 22.1. Paratuberculosis vaccine sales in the world in 2018.

Country	Doses
Australia	5,618,000
Spain	179,250
Republic of South Africa	159,000
The Netherlands^a	105,510
Greece	90,090
New Zealand	70,000
France	50,550
Iceland	45,000
United Arab Emirates^b	35,850
UK	30,000
Cyprus	24,000
Germany	22,250
USA^c	>22,400
Denmark^d	14,400
India^c	10,000
Portugal	9000
Oman^b	6000
Turkey^f	2100
World	6,493,000

Source: CZVaccines Gudair sales except otherwise indicated.

^a Mainly used in goats.

^b Some used in camels.

^c Used in cattle. The doses figure was provided by Dr Elisabeth Patton. The vaccine manufacturer, Boehringer Ingelheim, informed of discontinued vaccine production. ^d Used in the Faroe islands.

^e Vaccine licensed, but currently only in non-commercial production according to Professor Shoor Vir Singh. ^f Used in mouflon. Local company (Vetal) advertise a paratuberculosis vaccine, but did not answer enquiries.

production of most of these vaccines, it seems that all the international paratuberculosis vaccine market is supplied by CZVaccines (Table 22.1), with the exception of some production in Turkey (Vetal) and in India.

22.3

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Source: Behr Marcel A., Stevenson K., Kapur V. (eds.). Paratuberculosis: Organism, Disease, Control. 2nd edition. — CAB International,2020. — 439 p.. 2020

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