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Development of immunization trials against Pasteurella multocida

Development of immunization trials against Pasteurella multocida

Vaccine 32 (2014) 909–917 Contents lists available at ScienceDirect Vaccine journal homepage: www.elsevier.com/locate/vaccine Review Development o...

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Vaccine 32 (2014) 909–917

Contents lists available at ScienceDirect

Vaccine journal homepage: www.elsevier.com/locate/vaccine

Review

Development of immunization trials against Pasteurella multocida Tarek A. Ahmad a,∗ , Samar S. Rammah b , Salah A. Sheweita b , Medhat Haroun b , Laila H. El-Sayed c a b c

Scientific Support and Projects Section, Bibliotheca Alexandrina, Alexandria, Egypt Biotechnology Department, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt Immunology Department, Medical Researches Institute, Alexandria University, Alexandria, Egypt

a r t i c l e

i n f o

Article history: Received 23 September 2013 Received in revised form 4 November 2013 Accepted 18 November 2013 Available online 2 December 2013 Keywords: Pasteurellosis Pasteurella multocida Vaccine Immunotherapy

a b s t r a c t Pasteurellosis is one of the most important respiratory diseases facing economically valuable farm animals such as poultry, rabbit, cattle, goats and pigs. It causes severe economic loss due to its symptoms that range from primary local infection to fatal septicemia. Pasteurella multocida is the responsible pathogen for this contagious disease. Chemotherapeutic treatment of Pasteurella is expensive, lengthy, and ineffective due to the increasing antibiotics resistance of the bacterium, as well as its toxicity to human consumers. Though, biosecurity measures played a role in diminishing the spread of the pathogen, the immunization methods were always the most potent preventive measures. Since the early 1950s, several trials for constructing and formulating effective vaccines were followed. This up-to-date review classifies and documents such trials. A section is devoted to discussing each group benefits and defects. © 2013 Elsevier Ltd. All rights reserved.

1. Introduction Farm animals are very important to our daily lives. They are the main source for many of our basic needs such as proteins, vitamins, dairy products, eggs and also clothes. Animals, like people, suffer from diseases and need proper care from veterinarians. Animal infections cause severe disease outbreaks especially those caused by microbes that spread rapidly between domesticated animals. Although antibiotics are the main means to control such microbial incidences, their drawbacks highlight the need to find new potent ways to manage infections among animals [1]. Furthermore, the remains of those antibiotics in the animal products indirectly affect human health. The primary control of the infectious diseases of domesticated animals depends on good biosecurity. Vaccines are used simultaneously to prevent clinical symptoms of the diseases before infection and to control an infection at the population level. Veterinary vaccines play a major role in improving the health and welfare of companion animals and preventing animal-to-human transmission from both domesticated and wild animals [2]. Respiratory infections cause significant economic loss in sheep, goats, rabbits, poultry, and other farm animals. They often result from adverse physiological stress, or viral and bacterial infection interactions. Those infections cause high mortality rates that may reach 50% in infected animals [3]. One of the major causes in

∗ Corresponding author. Tel.: +20 1001701579. E-mail address: [email protected] (T.A. Ahmad). 0264-410X/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2013.11.068

the respiratory infections of farm animals is Pasteurella multocida. The disease causes pneumonia, genital infections, abscesses, and septicemia, and hence induces shortage in production and high mortality rates, therefore considerable economic loss. It appears in 20% of the entire stock of rabbits during summer, this increases in September and October to reach 50–60%, and then decreases gradually to enroll another rise in March and April. It reaches the lowest level during July and August [4,5]. However, in lambs it induces high mortality rates after 10–12 h of birth and manifests its outbreaks in sheep older than 3 months in May, June, and July [6]. This disease is responsible for 30% of the total cattle deaths worldwide [7,8] and losses of one billion dollars annually in beef cattle industry in North America alone [9]. Moreover enormous economic losses of pigs [10–12], poultry [13–15], and Chimpanzees [16] are due to P. multocida. Pasteurella species used to be classified as a member of genus Mannheimia. P. multocida is a non motile capsulated Gram-negative coccobacillary to rod shaped facultative anaerobic bacterium [17]. P. multocida serotyping is based on CPS, where the most pathogenic types are A1, A3, A1,3, A4, B2, and D1 [18–21]. It colonizes the nasopharynx, the respiratory tract and gastrointestinal tract of many animals and induces a disease called pasteurellosis. Under stress conditions, the commensal P. multocida becomes a pathogen by overwhelming the immune system of the host, proliferating in the nasopharynx and spreading to lungs [22]. It is an opportunistic pathogen responsible for fowl cholera (FC) of poultry, hemorrhagic septicemia (HS) of buffalo, pneumonia of lambs and goats, respiratory atrophic rhinitis of swine (AR) and purulent rhinitis (snuffles) of rabbits [23]. Although humans can be infected by handling carrier

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animals, it is a rare cause of adult meningititis. However P. multocida is the major cause of soft tissue infection after animal bites, especially those due to cats [24]. Pasteurellosis is a serious and highly contagious disease affecting domestic animals because its control methods are complex and treatment is expensive, lengthy and ineffective [5]. The use of antibiotics is a successful method to control Pasteurella infection. However, the microbial resistance limited antibiotics potency and about 80.5% of P. multocida showed to be resistant [25–27]. Scientist’s efforts were directed toward introducing new antibiotics to control resistant mutants, but unfortunately, pharmaceutical companies produced only few antibiotics specifically for Gram-negative bacteria [28], and therefore prevention was introduced as a successful tool for control [5,26,27,29]. 2. Prevention and immunotherapy The urgent need for a safe and potent control system led the scientists to use biosecurity protocols for the disease prevention. Although infection control methods proved to be a good way to minimize the infection spread and to reduce losses, these methods were not sufficiently effective to manage the spread of the disease [30]. Immunotherapies have made radical changes in the field of animal protection and treatment against infectious diseases. Immunoenhancers are products that enhance a number of non-specific natural killer cells or mechanisms, and hence the immune response increases. Cell-mediated immune response was achieved in chickens by the macrophage activating factor from T-lymphocytes [31]. Some components in the attenuated avirulent P. multocida [32] and the bacterium itself [33] simultaneously increased the phagocytic activity in the respiratory tract of chickens. But to the best of the authors’ knowledge no specialized products were used to increase the non-specific immune response against P. multocida. The following paragraphs classify the specific immunotherapy trials. 2.1. Passive immunization Several studies between 1975 and 1990 proved that the antisera raised against Clemson University avirulent P. multocida vaccine (CU vaccine), potassium thiocyanate extract of Pasteurella, and heat killed bacterium conferred protection to baby turkeys, rabbits and mice; respectively [34–36]. Studies in 1991, showed that the monoclonal antibodies (mAbs) raised against outer membrane proteins (OMP) of P. multocida were effective to immunize rabbits and mice against pasteurellosis, and to inhibit the bacterium proliferation in lungs [37–39]. Further studies starting from 1997 to 2007, proved that ammonium sulphate perceptible protein fractions (PSAP) of P. multocida [40], outer membrane protein H (OmpH) [41], Omp87 [42], and mixture of OMPs [43] of P. multocida proved to be effective against homologous infection by P. multocida in mice, rabbits and bovine. However, the antiserum against the bacterial glycoprotein provided cross-protection to chickens against heterologous challenge by different serovars [13]. Although, the protection potency was lacking or partial when mAbs were raised against lipopolysaccharide (LPS), in mice challenged with homologous pathogen [39,44], the polyclonal anti-idiotype antibodies against the protein that mimic the P. multocida LPS, protected mice against P. multocida infection [45]. 2.2. Active immunization Vaccination is the most effective and economic method to confer protection to animals against Pasteurella and minimize the symptoms of pasteurellosis [46]. The following paragraphs trace the development of those trials to construct effective vaccines against

Pasteurella spp. However to the best of the authors’ knowledge some preparations missed the clear description to be classified such as, the monovalent Pasteurella vaccine [47], the emulsified vaccine against swine pasteurellosis [48], the polyvalent oil-adjuvanted vaccine against birds pasteurellosis [49], the formulation prepared to prevent Pasteurella in cattle [50], the faction vaccine [51], and the subunit vaccine [52]. 2.2.1. Whole cell vaccines These vaccines are called the first generation vaccines. They can be used as a whole inactivated/killed, live attenuated or lysate bacterial cells to elicit the desired immune response. 2.2.1.1. Killed vaccines. The inactivated vaccines (bacterins) are prepared from Pasteurella killed by various ways such as heat, drying, formalin, phenol, or sodium azide. Heddleston and Hall [14] proved the high homologous potency due to the immunization of chickens using formalin-killed P. multocida, and examined the efficacy of the bacterial lysate in 1968 [53]. Starting in 1972 and for five years a series of experiments were performed by Heddleston and Rebers [54] on the formalin-killed host-passaged in vivo-propagated P. multocida. Although, they proved that the produced bacterin induce high cross-immunity against the bacterial challenge, the immunity was host specific [55] and was half of that conferred by the standard bacterium [56]. Later on the safety [57], and efficacy of the bacterium were tested in lambs [58]. However, in 2004, Dowling et al. [59] could not prove that lung exposure to formalin-killed P. multocida vaccine induced protective immunity in calves against homologous challenge. Emulsified water-in-oil bacterins prepared from formalin-killed P. multocida protected poultry from homologous challenge [60], reduced the number of infected turkeys from the avirulent vaccine [61], and induced only a systemic antibody titer in turkeys [62]. Scientists at the faculty of veterinary medicine in Belgium continued the trials on formalin-killed oil-adjuvanted Pasteurella vaccine (OAV) between 1980 and 1987. They proved that the preparation gave low immune response [63], and resulted in local tissue irritation and lession in mice [64]. However, other scientists demonstrated its potency in ducks [65], calves [66,67], and mice when heat killed Pasteurella is used [36]. The heat killed OAV showed reduced local reaction in poultry [68], and conferred 60% cross-protection to mice against homologous challenge [69]. Although it was confirmed that the degree of protection depends mainly on the number of doses [70,71], Gunawardana et al. [72] applied immunoblotting to study the advantages that adjuvants add to bacterin. Several studies were performed to evaluate the potency of different adjuvants [73]. The formalin-killed P. multocida was formulated with the Egyptian propolis to immunize rabbits against P. multocida infection and proved some improvement in the efficacy of the vaccine [74]. Moreover, OAV formulated with saponin provided strong humoral and cellular immune response against hemorrhagic septicemia in mice and calves [75]. The multiple emulsion vaccine (MEV), which was prepared by re-emulsifying of OAV with an equal volume of Tween 80, was a successful formulation for buffaloes protection against hemorrhagic septicemia over 6 month [7], and extended for one year in animals such as rabbits and calves [76,77]. Vaccination of calves with P. multocida bacterin formulated with toxoid conferred high immune response [78]. Although, buffaloes vaccinated with alumprecipitated vaccine a protection of 6 months, those vaccinated by OAV and double emulsion vaccines had a long-lasting protection that reached 12 months against hemorrhagic septicemia [7,79,80]. Moreover, cross-protection against heterologous challenge was achieved in buffalo immunized with OAV of P. multocida serotype B:2,5 [81]. Another approach for improving Pasteurella killed bacterin is the preparation of multivalent vaccines. Bivalent vaccines

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which consist of two serotypes of Pasteurella were effective in protecting rabbits from pasteurellosis [82], pentavalent vaccines decreased symptoms in calves [83], but not birds’ fowl cholera [44]. Although the bacterin of iron-depleted Pasteurella failed to induce cross-protection in poultry or rabbits [84,85], the full bacterin succeeded [86]. Several research projects failed to prove the effect of preparing vaccines for Pasteurella grown under different conditions [87]. Two years later in India, it was proven that ironinactivated P. multocida bacterin formulated with the bacterial DNA enhanced the protective potency of the poultry against fowl cholera [88]. Vaccination with bacterins has many disadvantages, as it lacks the ability to raise cross serotype protection, results in ineffective and short immunity, and immunized animals still suffer disease outbreak [23,74]. Moreover, bacterin results in inflammation at the site of injection [89]. 2.2.1.2. Live attenuated vaccines. Avirulent strains P. multocida were frequently used to formulate live attenuated vaccines against pasteurellosis. P. multocida serotypes A3 (P1059) [42,90], B3, and B4. Although they provided high protection to cattle for 13 months [76,91,92], they lacked the maternal potency [93]. The A/D strains elicited a potent response against homologous challenge in mice [94]. Moreover, mice showed tolerance when immunized with Pasteurella of pig origin [95]. P. multocida serotype B:2 grown under iron-restricted conditions offered a high protective potency against homologous infection in cattle and rabbits [96]. The acapsular serotype of P. multocida induced homologous and heterologous protection to mice and chicks [61,97,98]. The induction of mutations by mutagenic substances such as N-methyl-N -nitroN-nitrosoguanidine was a promising strategy to produce potent attenuated vaccines. Avirulent mutant strains of P. multocida M8283 [99] and M3G [100,101] offered turkeys high cross-protection against fowl cholera homologous and heterologous challenges when administered into drinking water. The use of the avirulent Clemson University strain of P. multocida (CU vaccine) in attenuated vaccines was extensively studied. High protective immune response was induced when turkeys and chickens were immunized with live CU vaccine [102–105]. In 1978, unlike the bacterin, the oral vaccination of turkeys with live CU vaccine showed to induce protective cellular and humoral responses in the respiratory organs against fowl cholera for four to six weeks without any adverse effects [62,106,107]. The survival rate of turkey hens that received the live CU vaccine reached 92% without any side effects [107], and that of chickens varied between 95 and 97.5% [108]. Therefore, Bierer and Eleazer [109] and later Heddleston [110] advised the use of live vaccine in the drinking water of turkeys to prevent fowl cholera. In 1977, Bierer [111,112] proved that increasing the concentration of CU vaccine administered in drinking water increases the degree of the vaccine’s protection level in turkeys. In 1977 it was proved that the efficiency of the CU vaccine increased by cofeeding the turkeys by sulfadimethoxine and ormetoprim [113] or lavamisole, the broad-spectrum anthelmintic [114]. Later on in 1980, it was proven that the number of immunizations was a distinct factor in increasing the efficiency of CU vaccine. Immunization of chickens with avirulent CU strain of P. multocida two or three times gave higher protection than one-time vaccination [115]. The route of immunization as well affected the efficiency of immunization. Oral vaccination of turkey breeder hens and broiler chickens with CU vaccine via both mouth and wing-web stick routes induced high immune response that lasted for 25–30 weeks with few adverse effects, but immunization of turkeys with high dose of the vaccine through wing-web route led to severe wing lesions [116,117]. Similar duration of protection was attained by subcutaneous vaccination of chickens [118], and oral vaccination

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in turkeys [119]. The factors of the bird’s age and type affected the potency. Although the potency of live CU vaccine was positively proved in turkeys and breeder-hens [120], chickens were not efficiently protected from fowl cholera [71], and when broiler-type chickens were immunized with live CU vaccine, antibody titer and immune response increased when vaccinated chickens increased in age [121]. Compared with CU vaccine, M-9, Minnesota and PM#1 and PM#3 avirulent P. multocida vaccine was not effective in protecting turkeys against fowl cholera [104,122], and has negative effects on body weight gain [123]. A further way to induce attenuation was the use of the streptomycin antibiotics. Streptomycin-dependent P. multocida vaccine provided complete protection for rabbits against homologous infection [78,124], and protected turkeys against fowl cholera [125]. However, live streptomycin-dependent P. multocida A:3 mutant protected rabbits from pasteurellosis induced by homologous and heterologous challenge [126–128], but not A:12 strain [129]. Streptomycin-dependent live P. multocida type A3 and B vaccine protected cattle against hemorrhagic septicemia without any adverse effects [130,131]. The deletion of the gene encoding the P. multocida toxins resulted in the production of an effective live attenuated vaccine against atrophic rhinitis in mice [132]. The live aroA deleted derivative of P. multocida serotype B:2 was used for calves and mice vaccination against hemorrhagic septicemia [44,80]. This safe preparation induced a protection against homologous challenge [133–135]. The marker-free aroA derivative of P. multocida elicited a cross-protective immunity against heterologous challenge [136]. Cross-protection was induced as well by using two live aroA mutants of P. multocida serotype 1 and 3 to protect in chickens against fowl cholera [137]. The aroA attenuated derivatives of two P. multocida serotype B:2 vaccines protected mice against hemorrhagic septicemia [80]. Immunization of pigs with live temperature-sensitive P. multocida mutant induced a humoral response against homologous infection [138]. While, immunization of mice with high doses of P. multocida cexA mutant (PBA875) conferred high protection against P. multocida infection. Moreover, vaccination of mice with acapsular P. multocida strain (AL18) induced high protective immunity against the wild-type infection. However vaccination with killed wild-type or killed AL18 failed to induce immunity [139]. Modifiedlive P. multocida vaccine of calves proved a good potency to increase antibody titer but did not improve the animal’s health or performance [140]. Another example is the live attenuated P. multocida mutant which expresses the N-terminal truncated fragment of P. multocida toxin (N-PMT). It had the potential to be used as powerful vaccine against wild-type challenge in pigs [141]. In 2012 an attenuated P. multocida derivative that only expresses N-PMT was used as a vaccine to prevent atrophic rhinitis due to its potency in inducing high antibodies level in mice [142]. The live attenuated vaccines main advantage is that they induce cross-serotype protection [23] and cellular immunity better than inactivated vaccines [143]. However, they may cause systemic infection, and disease outbreaks [144].

2.2.1.3. Digested bacterial lysates. In 1968, scientists discovered that the orally administrated P. multocida prepared from the lysate of killed organisms induced high resistance against the homologous challenge in chickens and turkeys [53]. The potassium thiocyanate extract (PTE) of P. multocida conferred high protection and reduction in disease severity in chickens against fowl cholera [145], in mice [146,147], and rabbits [35,148]. This protection is mainly due to the LPS and protein content of the extract [149]. In 1996, Suckow group [150] found that PTE of P. multocida coupled with cholera toxin (CT) enhanced the immune response against homologous

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challenge [151], especially when administrated subcutaneously [152] or incorporated with alginate microsphere [153]. Although, cell-free culture filtrate of P. multocida had high ability to immunize turkeys against pasteurellosis [154], it failed to induce cross-protection in turkeys against fowl cholera unless unfiltered [155]. This protection was mainly due to the endotoxin content [156,157]. The complete lysate of P. multocida heated at 56 ◦ C for 1 h provided full cross-protection to turkeys, while 50% cross-protection achieved by trypsin-treated lysate and no cross protection induced with pepsin-treated lysate [158]. The sonication-treated lysate provided higher protection than that of heat-treated one [69]. The controlled expression of cloned PhiX174 gene E of Gramnegative bacteria like P. multocida led to cells lysis and the formation of bacterial ghosts that were used as non-living candidate vaccines called “the recombinant ghost system” [159,160]. Rabbits and mice vaccinated with P. multocida ghosts had high immune response against homologous challenge [161]. This vaccination method has many advantages such as easy production method, safe, and effectiveness [160]. The addition of adjuvant to the supernatant fraction of P. multocida lysate enhanced its protective ability against heterologous and homologous challenge in turkeys. However using this adjuvant with complete lysate did not confer the same role in protection [162]. After two years, membrane vesicles solubilized with the whole supernatant of turkey-grown P. multocida gave variable degree of protection to turkey when challenged with P. multocida infection [163]. The most recent vaccine against P. multocida was based on the outer membrane protein vesicle (OMV). Those are tiny spherical bodies, that protrude from the outer membrane of Gram-negative bacteria. They consist of different membrane proteins, LPS and phospholipids. The intranasal immunization of mice by OMV induced a considerable heterologous humoral and mucosal immunity [164]. 2.2.2. Subunit vaccines Frequently called “second generation vaccines”, subunit vaccines are composed of individual immunogenic components of the pathogen such as the pathogen’s proteins and polysaccharides to elicit immunity. In 1972, Bapat and Sawhney [165] studied the capsular antigen of Pasteurella as vaccine candidate for rabbits. It was later proven that high doses of capsular antigens of P. multocida provided protection to cattle against HS which lasted for 14 months [166–168]. The lipopolysaccharide (LPS) of P. multocida was an effective tool to protect turkey from fowl cholera [169], mice from pasteurellosis [44,170,171]. It was proven that core LPS mutant of Escherichia coli (J5) can be used as useful cross-reacting prophylactic agent against pasteurellosis in rabbits [172]. The protective capacity of the protein fraction of Pasteurella was proven [173]. The immunization with a vaccine containing P. multocida toxin (PMT) protected pigs from rhinitis [174,175], and its formaldehyde toxoid derivative had a maternal potency [176–182]. The heat inactivated PMT protected rabbits from pasteurellosis [183]. However, the immunization of pigs with the dermonecrotic toxin (DNT) of P. multocida type D resulted in high humoral response [184], and protected rats from homologous challenge [185]. Moreover, P. multocida bacterin-toxoid (BT) induced a synergic protective immunity in rabbits higher than that induced with (PMT) alone [151]. The bacterin-toxoid formulation supplied rats with protection against the toxin of P. multocida serotype D [186]. The application of Pasteurella outer membrane protein (OMP) in vaccination started in 1991. The vaccination of rabbits with the OMP of P. multocida against the homologous challenge had the ability to minimize the severity of pneumonia and enhance phagocytosis in rabbits [38,96], cattle [187,188], but not in mice

[189,190] unless coupled with an adjuvant [191,192]. The vaccine based on iron-regulated OMP (IROMP) conferred protection to rabbits [193–195] and calves [196–198]. The native OmpH protein of P. multocida was used as well as a successful vaccine to immunize mice against homologous challenge since it induced high antibody titer and elevated proliferation ability of T-cells [199]. More recently, it was proven that the heat-modifiable OmpA family played a crucial role in enhancing the cellular response against P. multocida [200]. In addition to OMP, bacterial adhesins having a molecular weight of 39 kDa (Cp39) provided cross-protection for mice against homologous challenge [201,202]. In 2002, poultry and other animals were vaccinated against Gram-negative bacteria by a vaccine containing purified siderophore receptor proteins produced by strains of Pasteurella spp. [203]. In 2008, the use of subunit vaccine that contain Pasteurella lipoprotein E (PlpE), but not lipoprotein B was a revolutionary discovery in that time against P. multocida without any adverse effects [204–206]. In 1970, the combined vaccine which consists of culture filtrate, cell wall, and cytoplasm was a promising vaccine to protect turkeys against pasteurellosis [207], this developed later [140,208]. The adjuvancity effect of the PMT on other vaccines preparation was proved [209], especially with alginate encapsulated vaccines [210]. However, polyvalent Pasteurella vaccines induced high immunity and increased the resistance against P. multocida in mice, rabbits [211], calves [83], but not with sheep [212] even when coupled with oil adjuvant [213]. 2.2.3. Recombinant vaccines The use of recombinant vaccines or the so called third generation vaccines played a distinct role in producing vaccines against P. multocida. The first trial was in 1994, when a non-toxic recombinant derivative of the P. multocida toxin (rPMT) induced high response in pigs against rhinitis [214]. This developed by a vaccine consisting of three fragments of recombinant N-fraction of P. multocida toxin (rPMT-N), which provided high antibody titer, and high levels of maternal antibodies in the colostrums [215–218]. The use of novel combined vaccine that consists of rPMT and bacterin was successful to protect swine [219]. However in 1997, immunization of turkeys with recombinant P6-like protein lacked the ability to protect against avian fowl cholera [220]. Ten years later in Korea, Kim et al. [221] showed that the truncated recombinant OmpH protect pigs and mice against pasteurellosis [222–224]. Moreover, recombinant OmpA induced strong but non-protective immunity in mice [225]. In 2008, a study proved that the recombinant tobacco plant harboring OmpH protein of P. multocida A:3 can be used as a carrier system to develop plant-based vaccine against fowl cholera [226]. Chickens and mice were protected against pasteurellosis by using the recombinant adhesive protein (rCp39) [202,227]. Immunization with recombinant filamentous hemagglutinin peptides (rFHAB2) conferred high immune response and cross-protection against fowl cholera in turkeys [228,229] and HS in goats [230]. Recombinant P. multocida lipoprotein E (PlpE) induced cross immunity in mice and chickens against heterologous challenge [231]. The recombinant PlpE or OmpH and lipoprotein E (PlpE) genes fusion (PlpEC-OmpH) showed high ability to be used as vaccine for cattle against shipping fever due to P. multocida [232]. In 2011, Hussaini et al. [233] proved that recombinant clone ABA392 derived from P. multocida serotype B has the potential to provide 83% immunity to mice against hemorrhagic septicemia. Later on the same group proved that the expressed sub-clone CSI57 J of P. multocida serotype B could be a successful tool to vaccinate mice against HS [234]. 2.2.4. DNA vaccines These vaccines are known as the fourth generation vaccines. DNA vaccine derived from P. multocida toxin (PMT) gene showed a protective potency against homologous infection in mice and

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swine [235]. In India in 2011, outer membrane protein DNA vaccines were investigated to determine their potency to be used as successful vaccines against hemorrhagic septicemia of cattle and buffaloes [236]. In China in 2011, it was proven that OMP-DNA vaccines such as those of pOmpH, pOmpA of P. multocida could induce partial protection for chickens against avian pasteurellosis, while pOmpHA fusion vaccine conferred higher protection than that of attenuated vaccines [237]. In 2012, scientists tested the potency of three DNA vaccines that consisted of OmpH, PlpEN and PlpEC. Their study showed that these preparations were immunogenic but not protective against P. multocida in mice [232]. One year later, a group of scientists showed that divalent combination of pcDNA-OmpH + pcDNA-OmpA, pOmpH + pOmpA and fusion DNA vaccines had a promising ability to confer immune response in chickens against fowl cholera caused by avian P. multocida, however the monovalent DNA vaccines such as pcDNA-OmpH, pOmpH and pcDNA-OmpA, pOmpA had limited potency [238].

3. Conclusion Several microbial pathogens cause severe losses in the animal husbandry industry. The respiratory infections spread rapidly between the members of the troupes and disseminate to other ones resulting in large scale outbreaks. Pasteurella is a major respiratory infection in farm and wild animals, causing different symptoms of pasteurellosis that range from minor local infection to fatal septicemia. It is one of the most widespread ones, even in countries with low humidity and low temperature weathers that usually limit the spread of several pathogens. It is a highly contagious disease affecting domesticated animals, especially buffalos, poultry, and rabbits. Chemotherapeutic treatment of Pasteurella is expensive, lengthy, and ineffective, as well as being toxic to human consumers. Biosecurity measures may help to diminish the spread of the pathogen, but immunization methods are the most potent tools to prevent it. Although antisera against the microbial extract and OMP showed a considerable potency to control infections, vaccination protocols were the most effective to confer protection against the pathogen. The earliest vaccines against Pasteurella appeared in the mid1950s. Those were the formalin-killed in vitro grown bacteria that are still used till now as major commercial vaccines. They proved to confer a considerable protection against homologous infection for 6–8 weeks in different animals. It was confirmed that heat killed pathogens provide half-protection when compared to the formalin’s; an observation that suggests the major epitope of Pasteurella is a heat labile substance, such as proteins. Although attempts to produce host-passaged isolates induced high cross-immunity against the microbial challenges, it did not last for a longtime since the product was host specific and induced half protection when compared to the previous in vitro-propagated ones. Moreover, trials to produce bacterin from iron-deficient in vitro cultures failed since the vaccine never ensured full cross-protection. Oiladjuvanted formulation showed a variable efficiency in prolonging the bacterin action in cattle for 250 days, ducks, chickens, turkeys, rabbits but not sheep. The addition of saponin synergized that action. The level of protection was not affected by oil formulation but it was correlated to the number of administrations of the vaccine. Alum, Freund’s incomplete adjuvant, PMT toxoid, DNA, and propolis were used simultaneously to enhance the effect of bacterin. In general, the inactivated bacterin lacked the ability to confer cross-protection, long-term immunization and induced local inflammation at the site of injection. P. multocida were attenuated by their incubation with mutagenic substances, streptomycin, or subjected to gene deletion to produce avirulent live strains. Although the produced vaccine was

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unsafe when compared to bacterin, it induced cross-protection and cellular response better than the bacterin. However unlike bacterin, it had a therapeutic potency for infected animals. The attenuated vaccine offered a protection of thirty weeks in turkeys, thirteen months in buffaloes, and had a considerable potency when orally administered to poultry. Therefore trials to use attenuated vaccine as a booster for a primary bacterin dose were followed in some research. Starting in 1977, the bacterial lysates by potassium thiocyanate were shown to elicit a protective humoral response against the homologous challenge, especially when adjuvanted with cholera toxin and administered subcutaneously. Unlike pepsin-treated lysate, both the heated bacteria and the bacterial ghosts conferred a reasonable protection. This fact confirms that the main virulent factors of the bacterium are proteins in the cells wall. Subunit vaccines paved the way for use as safe candidates where CPS, LPS, siderophores, PMT, DNT, and lipoprotein E showed to confer reasonable antibody titer against the homologous challenge. Simultaneously, PMT was frequently used as adjuvant for bacterin and PTE. The PMT toxoid, OMP-A/H and the IROMP of strains B2 and B6 were able to induce high humoral and cellular responses. However, the protection obtained from those subunits was homologous, and their extraction was complicated. Therefore, recombinant trials to produce OmpA, OmpH, adhesive protein (Cp39), filamentous hemaglutinin peptides (FHAB2), fimbreal protein, N-fraction PMT, and lipoprotein E were followed since 1997. They conferred maternal potency, and high antibody titer against homologous challenge of the pathogen. As for being relatively cheaper for large scale veterinary use, the DNA vaccines were introduced to combat Pasteurella. DNA encoding for PMT, OmpA, OmpH, and lipoprotein E were tested for that purpose. Although the preparations induced both humoral and cellular responses, they were not protective unless introduced as divalent preparations for OMPs. Though, DNA vaccines appear promising; their use is limited by cost and lack of technological limitations. Although each trend of vaccine groups has its advantages and limitations, the ideal vaccine candidate would be one that confers long-term cross-protection for homologous and heterologous challenges, potent cellular and humoral response, therapeutic activity, prevent the septic shock due to the bacterium, as well as being nonreactogenic, easy to administer to the animals, easy to prepare and conserve, fully safe, and cheap. Although attenuated vaccine against P. multocida were unsafe, they were unique in offering heterologous protection and therapeutic activity. They shared the advantage of offering cellular response together with humoral one with DNA vaccines. Moreover, they may be orally administered, offer prolonged protection for almost a year, and are cheap and easy to produce. While all other type of vaccines lacked those unique criteria. Therefore, the trials to develop their use by reducing their harm are considerable aims. The proposed formulation that offers the majority of the ideal criteria of a vaccine against P. multocida is a dose of well adjuvanted killed vaccine to act itself as a vaccine against possible harm of the attenuated vaccine, followed by orally administered lifetime doses of the attenuated vaccine to attain the desired protection. As described previously, several formulations showed to enhance the activity of killed vaccines especially when supplemented with saponin, or when administered for specific time-intervals. Those regimens are trials of merit for further evaluation.

Acknowledgements The authors would like to thank Miss. Sherine Ahmed and Miss. Dalia Yakout volunteers at the Bibliotheca Alexandrina for the support they offered to retrieve all necessary articles. In parallel to,

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