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Registered Influenza Viral Vector Based Brucella ORIGINAL RESEARCH published: 01 July 2021 doi: 10.3389/fcimb.2021.669196 Registered Influenza Viral Vector Based Brucella abortus Vaccine for Cattle in Kazakhstan: Age-Wise Safety and Efficacy Studies Sholpan Ryskeldinova 1, Nadezhda Zinina 2, Zhailaubay Kydyrbayev 1, 2 1 1 1 Edited by: Bolat Yespembetov , Yerken Kozhamkulov , Dulat Inkarbekov , Nurika Assanzhanova , 1 1,3 2 4 Dongsheng Zhou, Aigerim Mailybayeva , Dina Bugybayeva , Makhpal Sarmykova , Berik Khairullin , 3,5 6 7 4 Beijing Institute of Microbiology and Kairat Tabynov , Aitbay Bulashev , Batyrbek Aitzhanov , Khairulla Abeuov , Epidemiology, China Abylay Sansyzbay 8, Tlektes Yespolov 3, Gourapura J. Renukaradhya 9, Steven Olsen 10, 11 3,5 Reviewed by: Angel Oñate and Kaissar Tabynov * Jerod Skyberg, 1 Infectious Disease Prevention Laboratory, Research Institute for Biological Safety Problems, Gvardeiskiy, Kazakhstan, University of Missouri, United States 2 3 Chuangfu Chen, Microbiology Laboratory, Research Institute for Biological Safety Problems, Gvardeiskiy, Kazakhstan, International Center for Vaccinology, Kazakh National Agrarian University (KazNAU), Almaty, Kazakhstan, 4 Infectious Disease Monitoring Shihezi University, China Laboratory, Research Institute for Biological Safety Problems, Gvardeiskiy, Kazakhstan, 5 Preclinical Research Laboratory With *Correspondence: Vivarium, M. Aikimbayev National Research Center for Especially Dangerous Infections, Almaty, Kazakhstan, 6 Department of Kaissar Tabynov Microbiology and Biotechnology, S. Seifullin Kazakh Agrotechnical University, Nur-Sultan, Kazakhstan, 7 Department of Clinical [email protected]; Veterinary Medicine, Kazakh National Agrarian University (KazNAU), Almaty, Kazakhstan, 8 Department of Biological Safety, [email protected] Kazakh National Agrarian University (KazNAU), Almaty, Kazakhstan, 9 Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University Specialty section: (OSU), Wooster, OH, United States, 10 Independent Researcher, McCallsburg, IA, United States, 11 Laboratory of Molecular This article was submitted to Immunology, Department of Microbiology, Faculty of Biological Sciences, University of Concepcion, Concepcion, Chile Clinical Microbiology, a section of the journal fl Frontiers in Cellular and A novel in uenza viral vector based Brucella abortus vaccine (Flu-BA) was introduced for Infection Microbiology use in cattle in Kazakhstan in 2019. In this study, the safety and efficacy of the vaccine was Received: 18 February 2021 evaluated in male and female cattle at different ages, and during pregnancy as a part of its Accepted: 07 June 2021 registration process. Our data demonstrated that the Flu-BA vaccine was safe after prime Published: 01 July 2021 – – Citation: or booster vaccination in calves (5 7 months old male and female), heifers (15 17 months Ryskeldinova S, Zinina N, old) and cows (6–7 years old) and was not abortogenic in pregnant animals. A mild, Kydyrbayev Z, Yespembetov B, localized granuloma was observed at the Flu-BA injection site. Vaccinated animals did not Kozhamkulov Y, Inkarbekov D, fl Assanzhanova N, Mailybayeva A, show signs of in uenza infection or reduced milk production in dairy cows, and the Bugybayeva D, Sarmykova M, influenza viral vector (IVV) was not recovered from nasal swabs or milk. Vaccinated Khairullin B, Tabynov K, Bulashev A, animals in all age groups demonstrated increased IgG antibody responses against Aitzhanov B, Abeuov K, Sansyzbay A, Yespolov T, Renukaradhya GJ, Brucella Omp16 and L7/L12 proteins with calves demonstrating the greatest increase Olsen S, Oñate A and Tabynov K in humoral responses. Following experimental challenge with B. abortus 544, vaccinates (2021) Registered Influenza Viral Vector Based Brucella abortus demonstrated greater protection and no signs of clinical disease, including abortion, were Vaccine for Cattle in Kazakhstan: Age- observed. The vaccine effectiveness against B. abortus 544 infection was 75, 60 and fi Wise Safety and Ef cacy Studies. 60%, respectively, in calves, heifers and adult cows. Brucella were not isolated from Front. Cell. Infect. Microbiol. 11:669196. doi: 10.3389/fcimb.2021.669196 calves of vaccinated cattle that were experimentally challenged during pregnancy. Our Frontiers in Cellular and Infection Microbiology | www.frontiersin.org1 July 2021 | Volume 11 | Article 669196 Ryskeldinova et al. Registered Brucella abortus Vectored Vaccine data suggests that the Flu-BA vaccine is safe and efficacious in cattle, including pregnant animals; and can therefore be administered to cattle of any age. Keywords: bovine brucellosis, influenza viral vector, vaccine, registration trials, protective efficacy, calves, heifers, cows INTRODUCTION challenge that was comparable to commercial attenuated vaccine strains (B. abortus S19 or RB51) (Tabatabai and Pugh, 1994; Brucella melitensis, Brucella abortus, B. suis and B. canis are all Oliveira et al., 1994a; Oliveira et al., 1994b; Oliveira and Splitter, considered to be zoonotic (O’Callaghan and Whatmore, 2011). 1996; Oliveira et al., 1996; Kurar and Splitter, 1997; Vemulapalli Brucellosis is one of the most common zoonotic diseases of et al., 2000a; Vemulapalli et al., 2000b; Al-Mariri et al., 2001; humans, with more than 500,000 cases reported annually. He et al., 2002; Leclercq et al., 2003; Oñate et al., 2003; Depending upon the system of controls and the socioeconomic Vemulapalli et al., 2004; Cassataro et al., 2005a; Cassataro et al., conditions, different countries have reported from 0.09 to 1,603 2005b; Oñate et al., 2005; Luo et al., 2006; Mallick et al., 2007; cases per million inhabitants (Pappas et al., 2006). Cabrera et al., 2009; Olsen et al., 2009; Pasquevich et al., 2009; Zhao B. abortus is the primary cause of brucellosis of cattle. Because of et al., 2009). However, the vaccine candidates were usually not tested its impact on human health, in Kazakhstan, regulatory actions for in large animal host species, such as cattle. With the exception of the cattle herds infected with brucellosis include quarantine double mutant strain B. abortus htrA cycL vaccine; and DNA and (Yespembetov et al., 2019). In cattle, brucellosis can be manifested RNA vaccine expressing Cu-Zn superoxide dismutase gene which by orchitis in males, but clinical signs are primarily in females and tested for immunogenicity in cattle, but not efficacy (Edmonds et al., include nonviable calves, abortions, retained placentas, and 2000; Sáez et al., 2008). A recombinant B. abortus RB51 vaccine infertility (O’Callaghan and Whatmore, 2011). Vaccination is an (overexpressing superoxide dismutase and glycosyltransferase effective tool for controlling brucellosis in livestock (Garin-Bastuji genes) was immunogenic in bison but not as efficacious as the et al., 1998), and is also effective in protecting human health in parental RB51 vaccine against challenge with the B. abortus strain endemic areas (Zinsstag et al., 2007). Currently, brucellosis vaccines 2308 (Olsen et al., 2009). Consequently, most B. abortus vaccine for cattle are live attenuated B. abortus strains (19, 82 and RB51). candidates have limited or no data available on their safety and Although these vaccines have high efficacy for cattle (protection efficacy in cattle, and therefore, are not available for field use. against abortion >70%, complete protection against infection >50%) With the goal of improving prevention of bovine brucellosis, (Confer et al., 1985; Stevens et al., 1995; Cheville et al., 1996; our group developed a novel vaccine based on an influenza viral Cardena et al., 2009; Ivanov et al., 2011), they have a number of vector (IVV) platform, which was registered and permitted for serious disadvantages including causing abortions in pregnant field use in Kazakhstan in 2019. We used influenza A viruses of animals, virulence in humans, and, with the exception of strain various subtypes as carriers for delivery of immunodominant RB51, cause high titers on brucellosisserologicteststhatcannotbe proteins of Brucella.Influenza viruses were chosen as a vector differentiated from responses of infected animals (Spink et al., 1962; because of their ability to infect cattle without causing clinical Beckett and MacDiarmid, 1985; Smith and Ficht, 1990). signs (Campbell et al., 1977; Brown et al., 1998; Gunning et al., Additionally, the strain RB51 is resistant to rifampicin, an 1999; Graham et al., 2002). The influenza A virus contains a antibiotic commonly used to treat brucellosis in humans (Schurig segmented genome consisting of eight negative-strand RNA et al., 1991). These characteristics of commercial vaccines have fragments. Of these, the smallest fragment (NS), encoding two limited their wide use in cattle in some countries. Development of proteins: viral nonstructural protein (NS1) and nuclear export an improved brucellosis vaccine for cattle with high efficacy, protein (Nep), is a convenient target for genetic manipulation improved safety characteristics, and the ability to be serologically since NS1 tolerates foreign sequences exceeding its own length differentiated from infected animals (DIVA) would be an (Kittel et al., 2004). On the other hand, Brucella constructs important advancement. encoding 124 amino acids from the N-terminal of the B. Previously, attempts to develop safe and effective B. abortus abortus immunodominant L7/L12 and Omp16 proteins vaccines have utilized attenuated mutants (Vemulapalli et al., 2000a; (Oliveira et al.,
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