Improving consumer protection against zoonotic diseases Phase II Project No: EuropeAid/133990/C/SER/AL

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1 ANNEX 13.9 Introduction Potential use of vaccine for Bovine Brucellosis control in Albania Brucella melitensis and Brucella abortus are the most relevant species in veterinary and public health and cause brucellosis in small ruminants and bovines, respectively. It is not uncommon, especially in conditions where bovines and small ruminants are bred in close proximity that Br. melitensis causes infection in bovines. Only smooth (S) Br.abortus S19 (for cattle) and Br.melitensis Rev1 (for sheep and goats) live vaccines have demonstrated their efficacy under most epidemiological conditions. A number of countries have eradicated brucellosis in domestic ruminants by sustained S19 and Rev1 vaccination of young animals in combination with test and slaughter. However, the success of this approach relies largely on favorable circumstances related to animal management, human habits and effectiveness of the Veterinary Services. Where these circumstances are not met because of economic, political, cultural and geographical circumstances, this strategy has failed or is not applicable. Nevertheless, even in these situations, vaccines can still be used to reduce prevalence and thus the burden of the disease on animals and human beings. Mass herd vaccination has been implemented in several countries and, although for various reasons these programs have often been discontinued, there are significant examples of areas where brucellosis prevalence has been reduced considerably (Blasco et.al., 2016). This document summarizes information from scientific literature for the vaccine available for bovine brucellosis control and present their advantages and disadvantages. Potential use of vaccines for bovine brucellosis control in Albania will depend on different factors including the causing agent of bovine brucellosis in Albania. General characteristics of vaccine The ideal Brucella vaccine shall have following characteristics (WHO, 1999): i. Be harmless and prevent infection with a single dose; ii. Not stimulate antibodies that interferes with sero diagnosis; iii. Not to be transmitted to humans or other animals, including not to contaminate meat, edible organs, milk and dairy products; iv. Be stable in vivo and vitro; v. Be readily cultivable under large scale fermentation condition; and vi. Be endowed of markers for an easy differentiation from field isolates. None of the currently available vaccines fulfills conditions from i to iv (Blasco et.al., 2016). 1

2 S19 - Standard procedure for vaccination (single subcutaneous dose of 5 10 x CFU/animal) induces long lasting protective immunity against Br. abortus infection in cattle. - Standard s/c vaccination dose may generate humoral response in proportion of vaccinated animals that interfere in serological tests, especially when adult animals are vaccinated. Humoral antibodies produced after single vaccination of adult animal may be persistent. In young animals this period is shorter. - Vaccination of pregnant cows may induce abortion and/or develops S19 infection of udder and then shading the vaccine bacteria with milk (Nicoletti, 1990). - Male animals shall not be vaccinated: vaccination of male animals can cause permanent genital infection when applied subcutaneously. - In controlled experiments, single dose confers 50% - 100% protection against bacterial challenges infecting 80% to 100% of unvaccinated controls (Barrio et al., 2009; Jacques et al., 2007; Manthei, 1959; Nicoletti, 1990). - It seems that revaccination with S19 does not significantly increase resistance (Beach et al., 1947; Berman et al, 1952). Potential benefits of revaccination outweighed by the increased interference with the serological tests. - Although of low virulence, S19 can infect humans. Potential use of S19 The above noted drawbacks may be avoided by choosing of optimal age (younger animals), dose (reduced dose) and route of application (conjunctival). Presently, S19 is marketed as full standard doses for subcutaneous administration, and formulations containing the reduced dose are not commercially available. This problem is largely administrative because, despite solid scientific evidence and practical experience, regulatory agencies consider the S19 conjunctival and subcutaneous formulations as different vaccines. Thus, the safety and efficacy dossiers of the S19 vaccines manufactured for subcutaneous vaccination do not legally apply to the conjunctival formulation, and no company has gone through the registration process as yet (Blasco et.al., 2016). (1) Reduced dose o Subcutaneous vaccination of young calves (between 4 and 5 months old) with a reduced dose (1/20th of the standard dose) substantially reduces the post-vaccinal anti-s-lps antibody responses, and lacks of relevant side effects (Alton and Corner, 1981) o Reduced dose when applied subcutaneously in adult cows minimizes the serological response but does not abrogate the vaccine-induced abortions and udder infections (Corner and Alton, 1981). Still, this protocol provides good immunity even under difficult conditions (Nicoletti, 1990; Nicoletti et al., 1978a). (2) Conjunctival route o The original conjunctival vaccination protocol is consisted of two reduced doses (each of 5 x 10 9 CFU/animal, and contained in a volume of μl) administered 2-6 months apart (Nicoletti et al., 1978b; Plommet & Fensterbank, 1976, 1984). Under field conditions, this method resulted in the same level of protection as the subcutaneous vaccination procedure with standard doses (Nicoletti, 1984; Plommet, 1984) and, in controlled experiments, it provided even better protection (Plommet, 1984; Plommet & Fensterbank, 1984). 2

3 RB51 o o The antibody response is decreased further when the S19 vaccine is administered through conjunctival instillation rather than subcutaneously (Fensterbank & Plommet, 1979; Plommet, 1984; Plommet & Fensterbank, 1976, 1984). The conjunctival vaccination can be implemented under most breeding conditions, and since it minimizes abortions and milk shedding when applied to pregnant cows (Nicoletti, 1990), it is the method of choice for whole-herd mass vaccination. The double conjunctival vaccination may be cumbersome under some circumstances, but experience has proved that a single conjunctival dose also provides protection useful to lead to eradication when combined with adequate test and slaughter (Blasco et.al., 2016). (3) Young animals o The conjunctival method is fully safe when applied to calves of 3-5 months of age, being the serological interferences reduced to a minimum. Accordingly, it is the method of choice when vaccination has to be implemented simultaneously with a test and slaughter eradication program (OIE, 2012). Potential Use of Br.abortus S19 vaccine against infection with Br.melitensis in cattle: One study demonstrated that S19 is efficient in control Br.melitensis infection in cattle. In the study, treatment of 16 Br.melitensis positive cows with a combination of oxytetracycline and streptomycin, and strain-19 vaccination of the remaining 79 seronegative cows stopped the transmission of brucellosis within the herd, even though reactor and non-reactor cows were kept together for 2 years. The antibiotic treatment produced cessation of excretion in 5 out of 11 B. melitensis-excretor cows and diminished the number of Brucellae excreted to the environment (Jiménez de Bagüés et al., 1991). Drawback of S19: - Vaccination of pregnant animals may induce abortions - Vaccination of male animals may induce permanent genital infections when applied subcutaneously - Vaccination induce humoral response which interfere with serological tests - Although of low virulence, the vaccine bacteria can infect humans - Recommended vaccination scheme induce immunity against Br.abortus infection. Protection level depends on the infection pressure and the level of contamination in the environment and it is similar to protection as S19 to abortion and infection (Cheville et al, 1993). - All vaccinated animals shall be revaccinated. It is recommended that four years after second vaccination animals are again vaccinated. Revaccination boost immunity and in highly infected conditions, revaccination every year is recommended (CZV). - RB51 confers similar protection as S19 to abortion and infection (Cheville et al., 1996b). - Young and adult female animals may be vaccinated, including pregnant animals. - Male animals shall not be vaccinated. - Vaccine bacteria is rapidly cleared from the bloodstream, as early as 2 weeks post-inoculation. 3

4 - Vaccine bacteria is not shed in the nasal secretions, saliva, or urine and therefore, the organism appears to be unable to spread from vaccinated to non-vaccinated animals through these routes. - Biosafety is considered as lower than from S19. No significant risk for humans. - Vaccine does not induce production of humoral antibody response that confers with the standard serological tests. Potential drawbacks: Some authors challenge the above characteristics of the RB51 vaccine, and in particular: (1) Protection - In the mouse model of brucellosis vaccines (Grilló et al., 2012), the protection provided by RB51 is markedly inferior to that of S19. In cattle, protection has been only moderate against mild challenges, and the few valid comparisons with S19 strongly suggest that RB51 is an inferior vaccine (Moriyón et al., 2004) quoted by Blasco et.al., Similarly, claims that RB51 has been useful in eradicating the disease in restricted areas (Martins et al., 2009; Saez et al. 2014) are not supported by appropriate control groups to discriminate the impact of vaccination from that of complementary measures implemented such as compulsory culling of the animals (Blasco & Moriyón, 2010; Martins et al., 2010) quoted by Blasco et.al., (2) Safety - Despite early claims on suitable safety in cows (Schurig et al., 2002), a high proportion of animals vaccinated during pregnancy can abort and excrete RB51 in the milk (Fluegel et al., 2013; Mainar-Jaime et al., 2008, 2011; OIE, 2012). The use of a reduced dose ( bacteria) represents an attempt to circumvent this problem by reproducing the good safety obtained with the S19 reduced dose, but RB51 does not produce suitable protection against B. abortus at this dose (Olsen, 2000). In fact, two reduced doses of RB51 given 3 months apart during calf hood, followed by yearly revaccination for six years, failed to eradicate the disease in dairy herds, despite applying complementary sanitary measures (Herrera et al., 2008), quoted by Blasco et.al., RB51 can cause infection in humans and precautions similar to those used in S19 or Rev1 vaccination should not be relaxed (Ashford et al., 2004; Villarroel et al., 2000), quoted by Blasco et.al., RB51 is rifampicin resistant. Rifampicin is an antibiotic which is in use for treatment of human brucellosis in Albania. - Infections with RB51 cannot be diagnosed serologically using the diagnostic tests available since these tests detect antibodies to the O-PS (Blasco et.al., 2016.). (3) Interference with serological tests weeks after RB51 vaccination about 50% of cattle remain positive in the lateral flow immunochromatography as well as in a S-LPS based indirect ELISA and, at lower proportion, also in the competitive ELISA (Mainar-Jaime et al, 2008). This proportion may increase up to 70% when individuals are revaccinated, a common practice in RB51 based vaccination strategies (Blasco et.al., 2016). (4) Protection against Br. melitensis - RB51 has not been tested against B. melitensis infections in cattle, but it does not protect small ruminants against this and other Brucella species (reviewed in Moriyón et al., 2004) quoted by Blasco et.al.,

5 Potential use of Rev-1 for vaccination of cattle: Neither the protective efficacy nor the safety of Rev1 has been determined in cattle, thus it is not recommended for immunizing cattle (OIE, 2012). Conclusion It is important to stress that no vaccination programme alone can successfully control and eradicate bovine brucellosis programme without comprehensive strengthening of other measures: identification and registration; movement control; hygiene and culling of infected animals. From the 2016 screening process, at least in two regions (Korca and Lezha) where field visits related to Bovine brucellosis were conducted, it became apparent that bovine brucellosis is only present in those herds that have so called open management and buy-in their animals without considering their health status, or whose herds have contact with animals of unknown health status during grazing. Such finding points to the effectiveness of the complementary measures for the control of the disease that is currently utilized by the farmers themselves. Such measures would be more effective when supported by the State Veterinary Services. This certainly apply to the large farms of categories I & II. References: Ashford, D. A., di Pietra, J., Lingappa, J., Woods, C., Noll, H., Neville, B., Weyant, R., Bragg, S. L., Spiegel, R. A., Tappero, J., Perkins, B. A. (2004). Adverse events in humans associated with accidental exposure to the livestock brucellosis vaccine RB51. Vaccine 22, Blasco, J.M., Moreno, E., Moriyon, I., (2016). Brucellosis vaccine and vaccine candidates. Veterinary Vaccines for Developing Countries. Chapter 5f. S. Metwally, Chief Editor, G. Viljoen and A. El Idrissi Co-Editors, FAO (Rome) (in press) Cheville NF, Olsen SC, Jensen AE, Stevens MG, Palmer MV, Florance AM. Effects of age at vaccination on efficacy of Brucella abortus strain RB51 to protect cattle against brucellosis. Am J Vet Res. 1996b;57(8): Fluegel, A.M., Cornish T.E., O Toole D., Boerger-Fields, A.M., Henderson, O.L., Mills K. W. (2013). Abortion and premature birth in cattle following vaccination with Brucella abortus strain RB51. J Vet Diagnostic Invest 25, Grilló, M. J., Blasco, J. M., Gorvel, J.-P., Moriyón, I. & Moreno, E. (2012). What have we learned from brucellosis in the mouse model. Vet Res. 43, 29. Herrera, E., Palomares, G. & Díaz-Aparicio, E. (2008). Milk production increase in a dairy farm under a six-year brucellosis control program. Ann New York Acad Sci 1149, World Health Organization. (1999). The Development of new/improved brucellosis vaccines: report of a WHO meeting, Geneva, Switzerland, December Geneva, Switzerland: Geneva: World Health Organization. Mainar-Jaime, R. C., Marín, C., de Miguel, M. J., Muñoz, P. M. & Blasco, J. M. (2008). Experiences on the use of RB51 vaccine in Spain. In Proceedings of the Brucellosis 2008 International Conference, Royal Holloway College, University of London, UK, pp Mainar-Jaime, R. C., Muñoz, P. M., de Miguel, M. J., Marín, C., Dieste L. & Blasco, J. M., (2011). Abortions induced by RB51 vaccine in beef cattle in central Spain: a descriptive study. In Proceedings of the Brucellosis 2011, 5

6 International Research Conference Including the 64th Brucellosis Research Conference. Buenos Aires, Argentina, September 21st to 23rd, Moriyón, I., Grilló, M. J., Monreal, D., González, D., Marín, C., López-Goñi, I., Mainar-Jaime, R. C., Moreno, E. & Blasco, J. M. (2004). Rough vaccines in animal brucellosis: structural and genetic basis and present status. Vet Res 35, OIE. (2012). Bovine brucellosis. In Manual of Diagnostic Tests and Vaccines for Terrestrial Animals, pp Edited by OIE. Olsen, S. C. (2000). Immune responses and efficacy after administration of a commercial Brucella abortus strain RB51 vaccine to cattle. Vet Therapeut 1, Villarroel, M., Grell, M. & Saenz, R. (2000). Reporte de primer caso humano de aislamiento y tipificación de Brucella abortus RB51. Arch Med Vet 32, World Health Organization. (1999). The Development of new/improved brucellosis vaccines: report of a WHO meeting, Geneva, Switzerland, December Geneva, Switzerland: Geneva: World Health Organization. 6