Vaccines and vaccination against fowl typhoid and pullorum disease: An overview and approaches in developing countries

Vaccines and vaccination against fowl typhoid and pullorum disease: An overview and approaches in... SUMMARY In poultry, host-specific Salmonella infections cause fowl typhoid and pullorum disease, which are severe systemic diseases of chickens that result in severe problems and high mortality and produce economic losses in developing countries. Fowl typhoid and pullorum disease have reemerged in recent years in developing countries, and birds of any age can be infected. Developing countries have established sanitary measures and official programs to prevent and control both diseases; however, there are cyclic or seasonal outbreaks related to disease management. An overview of the current situation and future perspectives regarding live attenuated vaccines against fowl typhoid and pullorum disease are discussed. Fowl Typhoid and Pullorum Disease Situation in Developing Countries Host-specific Salmonella infections cause fowl typhoid (FT) and pullorum disease (PD) in poultry, but are avirulent in mammals. These diseases are distributed worldwide [1] and have been eradicated in many developed countries [2]; however, they remain responsible for economic losses in the poultry industry in developing countries in Africa, Asia and Latin America [3]. Although many developed countries have successfully eradicated host-specific Salmonella (FT and PD) via testing and slaughtering at infected farms, the scenario is different in developing countries, where eradication is not realistic and may not be an option. There are many differences between developing and developed countries. First, sanitary programs for controlling FT and PD are different in developing countries, and information regarding the incidence or prevalence of infections is lacking. Most developing countries use passive surveillance, collecting data from different sources, but underreporting is a big problem with this strategy. Few developing countries have active surveillance for Salmonella Gallinarum (SG) and Salmonella Pullorum (SP) as part of their national monitoring programs for poultry diseases. Therefore, the official data submitted to OIE (World Animal Health Organization) do not always reflect what occurs in the field. Based on 2005 to 2015 data from the OIE database [4] recovered from with WAHIS Interface and OIE notification procedure [5] FT was never reported in 2 countries, and 4 countries had no information on this disease. The disease was present in 22 territories out of 59 reporting countries in Africa. The Americas region included 52 reporting territories, but 14 territories did not have any kind of available information; FT was never reported in 11 territories, was absent in 14 territories, and was present in only 9 countries. In Asia (46 reporting territories), FT was never reported in 5 countries, and 2 territories did not show any information; FT was present in 14 territories and absent in 32 territories. In Oceania (31 reporting territories), 20 territories did not have information, and FT was never reported in 6 territories. In Europe (53 reporting territories), 5 countries never reported FT during 2005 to 2015, and there were no countries without any kind of information. Regarding PD, only one country in Africa (59 territories) never reported the disease. In the Americas (52 reporting territories), 11 never reported PD, and there was no information available from 17 countries. In Asia (46 reporting territories), one country never reported PD, and 4 countries did not have any kind of available information. In Europe (54 reporting territories), 3 countries never reported the disease, and there was no available information for 2 countries. Consequently, data available on outbreaks in developing countries from official sources suggest that these diseases are underreported [6]. This situation is exacerbated in developing countries by a lack of active surveillance in commercial flocks and a lack of monitoring or surveillance for ornamental, hobby, backyard, game, or wildlife birds, which can remain a constant reservoir of SP and SG. Furthermore, these non-commercial bird species are not included in national poultry programs, except for avian influenza in some countries. The second situation is related to managing the control of FT and PD caused by SP and SG and the use of antimicrobial therapy against both diseases. It is important to note that antimicrobial therapy is still being used for FT and PD [6] at the farm level as an alternative means of reducing mortality; however, antibiotic therapy does not clear the infection from a flock. The administration of antimicrobials at low doses for extended durations for growth promotion and disease prevention has been linked to the global crisis of antimicrobial resistance [7]. Interestingly, despite scientific evidence that antimicrobials do not clear Salmonella infections and that they can be responsible for carriers, antimicrobial resistance, and residues in egg production [8], antimicrobial products continue to be used to reduce flock mortality in developing countries. Recent investigations using fluoroquinolones in a controlled experimental model in Brazil [9] confirmed that chemotherapy during outbreaks facilitates the persistence of SG in poultry. The worst effect of therapeutic treatments and dosage is the use of different kinds of antimicrobial products, or mixtures of more than one active ingredient, based only on clinical evidence without strain isolation or knowledge of pharmacological properties, Minimum inhibitory concentration (MIC) measurements, or susceptibility tests of isolates. Consequently, antimicrobial-resistant strains have appeared, and multidrug-resistant (MDR) isolates of SP have been reported [10]. MDR strains have been a major impediment in the treatment of FT using antimicrobials [3, 11]. A second challenge relates to scientific evidence that host stress drives Salmonella recrudescence associated with neuroendocrine responses and the direct effect of stress mediators on bacteria and gene expression, driven by the scsA gene to respond to the host stress hormone cortisol inducing the macrophage cytoskeletal rearrangements that facilitate intracellular bacterial replication [10, 11, 12]; thus, Salmonella can respond to subtherapeutic pressure by increasing its virulence and disease severity [13]. The third situation has a legal and economical basis. Developing countries have programs for controlling, preventing, and eradicating FT and PD, but the legal framework is not updated according to new approaches, the epidemiological situation, or new tools for diagnosis or prevention. Some local regulations permit vaccination using inactivated vaccines against Salmonella. These products were useful for many years, but live Salmonella vaccines based on the 9R strain (introduced in the 1950s) later appeared and were used in some countries. Attenuated Salmonella Enteritidis (SE) vaccines (introduced in the 1990s) with demonstrated efficacy to prevent and control SE and effective cross protection against SG infection were also introduced. On the other hand, eradication programs in developing countries do not include economic compensation for poultry producers. Vaccines and Vaccination for Controlling Fowl Typhoid and Pullorum Disease in Poultry There is ongoing interest in finding ways to prevent and control flock infection, and hence, vertical and horizontal transmission. Vaccination has been the most practical and effective strategy for controlling FT in developing countries where SG is endemic [14], and new attenuated strains are being investigated. Inactivated products are killed bacteria, using different adjuvants to improve their immunogenic properties, and these products have been used to protect poultry and their progeny against field challenges; however, they do not elicit a cell-mediated immune response, which is indispensable for the clearance of Salmonella [15]. They increase circulating antibodies, reducing Salmonella in the external milieu and decreasing excretion in feces. A group of experimental products called bacterial ghosts is an innovative approach to non-living vaccine technology that can aid FT control programs. These ghosts are believed to maintain all functional and antigenic structures in the envelope, including bioadhesive properties and the capability to induce a complete immune response [16]. Regarding this new candidate, an efficacy study showed that mortality was controlled more efficiently in the group vaccinated intramuscularly than in the unvaccinated and orally vaccinated groups. The development of a cell-mediated immune response after vaccination was demonstrated, and challenge results were evaluated using mortality and gross lesions scores [17]; however, there were no assessments of challenge strain persistence in cecal content, liver, or spleen in vaccinated and challenged birds, so further studies are needed. Live attenuated vaccines were first developed to prevent FT in 1956, which is when the SG rough strain was developed [18]; however, the vaccine should be avoided because the nature of its attenuation is not known [19, 20]. The SG 9R (SG9R) vaccine strain still results in systemic disease, and it was suggested that variants can cause some outbreaks, indicating that gene mutations aceE and rfsj could explain the reversion to a more virulent phenotype [21]. The use of SG9R in poultry outbreaks in the field in clinically healthy birds has a high frequency of increasing the virulence of the SG9R strain, which might be explained by the interaction among the circulating strain, the vaccine strain, and the host; certain environmental conditions also may be involved in the reversion of the virulence of the vaccine strain. Later, many attempts to prevent FT by vaccination with SG strains were developed; some mutant strains were tested (Table 1), but they are not commercially available, except for the SG9R strain. As a safe alternative, an attenuated live vaccine containing a metabolic drift mutant strain of SE was used with success against FT in layers [35, 36]. Table 1. Live attenuated mutant strains for controlling fowl typhoid. Salmonella serotype Mutant strain/attenuation Advantages Disadvantages aroA mutant [20] Highly attenuated for chickens Poor protection after intramuscular administration, no protection after oral administration aroA-serC mutant [22] Highly attenuated, 100% protection in 106 challenge Intramuscular administration cobS and cbiA mutant [23, 24] Oral vaccination, reduced mortality in brown chickens after SG challenge Lesions in organs can be observed, one vaccination did not affect shedding of an SE challenge, vaccination does not prevent cecal colonization of SE challenge strain crp mutant [25] Suggested protective ability fur mutant [14] Avirulent in chicks, excellent protection when given orally to Rhode Island Red chickens Not effective when given orally to older birds Salmonella Gallinarum lon cpxR mutant [26] Double mutant, no mortality after challenge Egg contamination and persistence were not evaluated, safety concern lon cpxR asd mutant [27] Induced acquired immunity and protected birds after challenge, gross lesions in spleen and liver 3 d post inoculation, safer than lon cpxR mutant and SG9R Intramuscular administration, mucosal immunity was not evaluated SG metabolic drift mutant [28] Double marker demonstrated no differences compared with the control group, vaccinated chickens were protected against challenge Single marker showed residual gross lesions in liver or spleen, OD readings in serum samples of IgG was observed 15 d post vaccination, Rif1-Sm10 strain does not show protection against challenge metC mutant [29] No mortality or clinical signs Further investigation of efficacy of metC mutant as potential genetically engineered live vaccine candidate nuoG mutant [30] Highly attenuated Poor protection, high persistence, less invasive Semi-rough lipopolysaccharide structure (9R strain) [18, 19, 21] Reduced mortality Undefined mutation, residual virulence speB speE mutant [31] Polyamine biosynthesis is essential for oral infection of SG Virulence restored by reintroducing speB gene on a plasmid E-lysis system [32] Safe for chickens Subcutaneous administration, reduction of mortality after 2 vaccinations, inactivated product rpoS, hmp and ssrAB triple-deletion mutant [33] Complete protection against challenge with wild-type SG, no mortality in birds inoculated with 108 CFU Vaccine strain isolation in liver and spleen were higher than levels with vaccination using SG9R sipC srp deletion mutant [34] Protective efficacy against mortality Intramuscular vaccination Salmonella Enteritidis Metabolic drift mutant [35, 36] Oral administration, effective in presence of maternal antibodies, prevented SE infections, clearance of SG from the host, environmental safety Cannot be applied with anticoccidial vaccines Salmonella serotype Mutant strain/attenuation Advantages Disadvantages aroA mutant [20] Highly attenuated for chickens Poor protection after intramuscular administration, no protection after oral administration aroA-serC mutant [22] Highly attenuated, 100% protection in 106 challenge Intramuscular administration cobS and cbiA mutant [23, 24] Oral vaccination, reduced mortality in brown chickens after SG challenge Lesions in organs can be observed, one vaccination did not affect shedding of an SE challenge, vaccination does not prevent cecal colonization of SE challenge strain crp mutant [25] Suggested protective ability fur mutant [14] Avirulent in chicks, excellent protection when given orally to Rhode Island Red chickens Not effective when given orally to older birds Salmonella Gallinarum lon cpxR mutant [26] Double mutant, no mortality after challenge Egg contamination and persistence were not evaluated, safety concern lon cpxR asd mutant [27] Induced acquired immunity and protected birds after challenge, gross lesions in spleen and liver 3 d post inoculation, safer than lon cpxR mutant and SG9R Intramuscular administration, mucosal immunity was not evaluated SG metabolic drift mutant [28] Double marker demonstrated no differences compared with the control group, vaccinated chickens were protected against challenge Single marker showed residual gross lesions in liver or spleen, OD readings in serum samples of IgG was observed 15 d post vaccination, Rif1-Sm10 strain does not show protection against challenge metC mutant [29] No mortality or clinical signs Further investigation of efficacy of metC mutant as potential genetically engineered live vaccine candidate nuoG mutant [30] Highly attenuated Poor protection, high persistence, less invasive Semi-rough lipopolysaccharide structure (9R strain) [18, 19, 21] Reduced mortality Undefined mutation, residual virulence speB speE mutant [31] Polyamine biosynthesis is essential for oral infection of SG Virulence restored by reintroducing speB gene on a plasmid E-lysis system [32] Safe for chickens Subcutaneous administration, reduction of mortality after 2 vaccinations, inactivated product rpoS, hmp and ssrAB triple-deletion mutant [33] Complete protection against challenge with wild-type SG, no mortality in birds inoculated with 108 CFU Vaccine strain isolation in liver and spleen were higher than levels with vaccination using SG9R sipC srp deletion mutant [34] Protective efficacy against mortality Intramuscular vaccination Salmonella Enteritidis Metabolic drift mutant [35, 36] Oral administration, effective in presence of maternal antibodies, prevented SE infections, clearance of SG from the host, environmental safety Cannot be applied with anticoccidial vaccines View Large Table 1. Live attenuated mutant strains for controlling fowl typhoid. Salmonella serotype Mutant strain/attenuation Advantages Disadvantages aroA mutant [20] Highly attenuated for chickens Poor protection after intramuscular administration, no protection after oral administration aroA-serC mutant [22] Highly attenuated, 100% protection in 106 challenge Intramuscular administration cobS and cbiA mutant [23, 24] Oral vaccination, reduced mortality in brown chickens after SG challenge Lesions in organs can be observed, one vaccination did not affect shedding of an SE challenge, vaccination does not prevent cecal colonization of SE challenge strain crp mutant [25] Suggested protective ability fur mutant [14] Avirulent in chicks, excellent protection when given orally to Rhode Island Red chickens Not effective when given orally to older birds Salmonella Gallinarum lon cpxR mutant [26] Double mutant, no mortality after challenge Egg contamination and persistence were not evaluated, safety concern lon cpxR asd mutant [27] Induced acquired immunity and protected birds after challenge, gross lesions in spleen and liver 3 d post inoculation, safer than lon cpxR mutant and SG9R Intramuscular administration, mucosal immunity was not evaluated SG metabolic drift mutant [28] Double marker demonstrated no differences compared with the control group, vaccinated chickens were protected against challenge Single marker showed residual gross lesions in liver or spleen, OD readings in serum samples of IgG was observed 15 d post vaccination, Rif1-Sm10 strain does not show protection against challenge metC mutant [29] No mortality or clinical signs Further investigation of efficacy of metC mutant as potential genetically engineered live vaccine candidate nuoG mutant [30] Highly attenuated Poor protection, high persistence, less invasive Semi-rough lipopolysaccharide structure (9R strain) [18, 19, 21] Reduced mortality Undefined mutation, residual virulence speB speE mutant [31] Polyamine biosynthesis is essential for oral infection of SG Virulence restored by reintroducing speB gene on a plasmid E-lysis system [32] Safe for chickens Subcutaneous administration, reduction of mortality after 2 vaccinations, inactivated product rpoS, hmp and ssrAB triple-deletion mutant [33] Complete protection against challenge with wild-type SG, no mortality in birds inoculated with 108 CFU Vaccine strain isolation in liver and spleen were higher than levels with vaccination using SG9R sipC srp deletion mutant [34] Protective efficacy against mortality Intramuscular vaccination Salmonella Enteritidis Metabolic drift mutant [35, 36] Oral administration, effective in presence of maternal antibodies, prevented SE infections, clearance of SG from the host, environmental safety Cannot be applied with anticoccidial vaccines Salmonella serotype Mutant strain/attenuation Advantages Disadvantages aroA mutant [20] Highly attenuated for chickens Poor protection after intramuscular administration, no protection after oral administration aroA-serC mutant [22] Highly attenuated, 100% protection in 106 challenge Intramuscular administration cobS and cbiA mutant [23, 24] Oral vaccination, reduced mortality in brown chickens after SG challenge Lesions in organs can be observed, one vaccination did not affect shedding of an SE challenge, vaccination does not prevent cecal colonization of SE challenge strain crp mutant [25] Suggested protective ability fur mutant [14] Avirulent in chicks, excellent protection when given orally to Rhode Island Red chickens Not effective when given orally to older birds Salmonella Gallinarum lon cpxR mutant [26] Double mutant, no mortality after challenge Egg contamination and persistence were not evaluated, safety concern lon cpxR asd mutant [27] Induced acquired immunity and protected birds after challenge, gross lesions in spleen and liver 3 d post inoculation, safer than lon cpxR mutant and SG9R Intramuscular administration, mucosal immunity was not evaluated SG metabolic drift mutant [28] Double marker demonstrated no differences compared with the control group, vaccinated chickens were protected against challenge Single marker showed residual gross lesions in liver or spleen, OD readings in serum samples of IgG was observed 15 d post vaccination, Rif1-Sm10 strain does not show protection against challenge metC mutant [29] No mortality or clinical signs Further investigation of efficacy of metC mutant as potential genetically engineered live vaccine candidate nuoG mutant [30] Highly attenuated Poor protection, high persistence, less invasive Semi-rough lipopolysaccharide structure (9R strain) [18, 19, 21] Reduced mortality Undefined mutation, residual virulence speB speE mutant [31] Polyamine biosynthesis is essential for oral infection of SG Virulence restored by reintroducing speB gene on a plasmid E-lysis system [32] Safe for chickens Subcutaneous administration, reduction of mortality after 2 vaccinations, inactivated product rpoS, hmp and ssrAB triple-deletion mutant [33] Complete protection against challenge with wild-type SG, no mortality in birds inoculated with 108 CFU Vaccine strain isolation in liver and spleen were higher than levels with vaccination using SG9R sipC srp deletion mutant [34] Protective efficacy against mortality Intramuscular vaccination Salmonella Enteritidis Metabolic drift mutant [35, 36] Oral administration, effective in presence of maternal antibodies, prevented SE infections, clearance of SG from the host, environmental safety Cannot be applied with anticoccidial vaccines View Large Two experimental vaccines were developed in the 1990s, but they had poor protection and environmental persistence. First, an aroA mutant of SG was tested, and it was shown to be highly attenuated when inoculated orally and intramuscularly. It persisted in different tissues for no more than 9 d, but the protection in birds was poor compared to that of the SG9R strain, so it was not useful for protecting chickens [20]. The second vaccine was a nuoG mutation introduced into a virulent SG strain [30]; its protection was similar to or better than that of SG9R, and the degree of invasiveness in the intestine, liver, and spleen was reduced compared to that in the wild-type strain. However, the vaccine strain persisted for at least 6 weeks. Two yr later, in 2000, an aromatic dependent mutant of a wild-type SG strain that was lysogenic for P22 sie was developed, and it was the first report of attenuation associated with lysogenization. The SL5828 strain was administered intramuscularly and had excellent results in immune protection studies, conferring 100% protection against the homologous strain [22]. In 2007, a metC mutant of SG was constructed, and various experiments were carried out to assess the effects of this mutation on virulence and invasiveness. This study suggested that the metC mutant of SG could be a potential genetically engineered vaccine candidate against FT [29]. Another mutant of SG was developed and evaluated in Brazil [23, 24] with deletions in genes cobS and cbiA, which are involved in the biosynthesis of cobalamin, and this mutant strain was tested for efficacy in 2 experiments performed separately. This mutant strain was administered once or twice and showed efficacy in brown chickens against mortality caused by a SG wild-type challenge, whereas its efficacy in white chickens was demonstrated after one or 2 vaccinations. This experimental vaccine strain administered once at 5 d of age in brown chickens conferred 85% protection against mortality caused by a homologous wild-type strain challenge compared to the unvaccinated and challenged group, and 75% protection when administered twice (at 5 and 25 d of age). This ΔcobSΔcbiA strain induces a systemic response of IgY, suggesting that Th1 and Th2 responses are produced in vaccinated birds [24]. The safety and efficacy of another double mutant strain (lon/cpxR) was compared with SG9R in 6-week-old hens [26], and it showed that the vaccine was safe and had more efficient protection than SG9R with significantly decreased lesions in organs and recovery of the challenge strain. The efficacy of a live attenuated SG vaccine strain with deletion of the global regulatory gene fur was evaluated in Rhode Island Red chicks and brown leghorn layers [14]. The ferric uptake regulator (fur) protein acts as a repressor of many genes and is essential for the virulence of SG; fur deletion resulted in a complete attenuation of SG that was as effective as a live recombinant vaccine against FT influenced by the administration route. This vaccine protected Rhode Island Red chickens when it was administered orally in young chickens or intramuscularly in brown leghorn chickens [14]. A new vaccine candidate that secretes heat-labile enterotoxin B subunit protein was evaluated for safety, immunogenicity, and protective efficacy against FT in 2014 [27]. The live attenuated vaccine against SG, identified as JOL1355, was administered intramuscularly; it was safe, displayed no adverse effects in vaccinated chickens, and exhibited bacterial persistence in the spleen for 7 d post inoculation and small gross lesions up to 3 d post inoculation [27]. The vaccine strain had a positive effect on the complete clearance of the challenge wild-type SG strain from internal organs observed 14 d post inoculation; thus, this vaccine could be an excellent tool to induce acquired immunity and clear bacteria from infected birds. In 2014 [31], another SG strain was evaluated to explore whether polyamines are essential to the virulence of SG, and these results showed new ways for developing treatments for FT to inhibit these enzymes. A novel approach was developed to generate SG ghosts and assess their vaccine potential using a prime-booster vaccination [32]; however, inactivated vaccine administration can be a disadvantage compared to other available SG oral live attenuated vaccines. Live attenuated metabolic drift mutants of SG vaccines with a single or double attenuating marker have been tested, and they showed homologous protection and clearance of wild-type SG 14 d post challenge, which can be attributed to the clearance of the challenge strain by cellular mediated immunity. Mutants with 2 attenuating markers assure safety, and the probability of back mutation can almost be excluded [28]. A triple-deletion mutant was tested as a live vaccine candidate in Lohmann layer chickens; the results showed that the SGΔ3 mutant conferred complete protection against challenge with virulent SG [35], indicating that this strain could be a promising candidate for a live attenuated vaccine against FT. The triple mutant was used orally or subcutaneously, and the results indicated that the strain conferred a level of protection similar to SG9R; however, bacterial counts were higher than those in SG9R in the liver and spleen. Finally, a live attenuated SG spiC and crp deletion mutant was tested, and efficient protection was observed based on mortality and clinical symptoms [34]. On the other hand, there is a metabolic drift mutant strain of SE that has demonstrated efficacy against FT in some African and Latin American countries. The vaccine must be administered by drinking water 3 times. The vaccine strain was tested in layers using different vaccination schedules, and it was demonstrated that the SE metabolic drift mutant strain contained in the vaccine was able to protect hens against a SG challenge [35]. The vaccine was safe, it persisted in the environment for 12 d after first vaccination, and booster applications reduced excretion of the vaccine strain. Other studies on the efficacy of this vaccine were carried out in Morocco against SG infection [36], confirming the cross protection against FT in layers under controlled and field conditions. In contrast to the studies performed in Argentina [35], the vaccine strain was never re-isolated after vaccination in the environment or from internal organs [36]. There was a reduction of mortality in birds challenged at 20 wk (7.5% mortality in the vaccinated group), and the mortality was only 7.69% in birds challenged at 32 wk of age [36]. The most important assessment of the Moroccan study was the clearance of the challenge strain, and survivors of the SE metabolic drift mutant live vaccine cleared the SG challenge strain by 86.5% at the 23rd wk and 89% at the 34th wk challenge compared to the control group, which had an average of 6% for unvaccinated groups. Unpublished field experiences in Latin America by the author demonstrated that vaccination is efficacious during FT outbreaks, reducing mortality and clearing the bacteria from affected birds, when it is administered in poultry houses with good farming practices. It is important to note that vaccination efficacy is directly related to biosecurity measures, sanitation, and hygienic conditions. Vaccines against PD were not developed until this century. A sipC mutant has been described as a potential new vaccine candidate for use in chickens against PD [37] because the mutant strain (spiC::km) was attenuated and highly immunogenic compared to the parent strain, did not induce clinical signs for 4 wk, and was not isolated from organs beyond 8 d post infection. In 2015 [38], SPI-2 (Salmonella pathogenicity island 2) mutant of SP (S06004ΔSPI2) was tested for efficacy on 2-day-old chickens, and no clinical signs or differences in body weight were observed [38]. The mutant identified as S06004ΔSPI2 could not be isolated from the liver more than 2 wk post vaccination or from the spleen more than 3 wk post vaccination; meanwhile, organs from the group infected with the parent strain were positive until 3 wk post infection. Interestingly, chickens orally vaccinated with the mutant SP strain were challenged intramuscularly 10 d post vaccination using the parent strain of SP and SG strain SG9. The survival rate was 100% in the vaccinated group with the mutant strain of SP (S06004ΔSPI2) and 60% in the control group vaccinated with phosphate buffer saline (PBS) and challenged with the parent strain of SP; in the case of vaccination using S06004ΔSPI2 and challenged with SG9, the survival rate was 100% compared to the control group vaccinated with PBS and challenged with the same strain, where this value was 30%. This first study showed the potential of the S06004ΔSPI2 strain as a live attenuated oral vaccine against FT and PD [38]. An additional trial was conducted using this strain, but in this case, the vaccination was performed intramuscularly on 2-day-old white chickens [39], and the challenge occurred 10 d post vaccination by an intramuscular route. The persistence results of vaccine strain S06004ΔSPI2 indicated that this mutant can persist for 14 d, except for one spleen sample that was positive at d 21 post vaccination. Slight clinical signs were observed in groups vaccinated with S06004ΔSPI2 and challenged with SP and SG9, but 3 to 7 days post challenge, the birds did not show any clinical signs. Serum levels of IgG were significantly higher in the vaccinated birds during all observation periods, and cellular immune responses (examined by peripheral mononuclear proliferation assay) were elevated by 14 d post vaccination. Vaccinated birds showed a survival rate of 90% in the group vaccinated with the S06004ΔSPI2 strain and challenged with the SP parent, whereas a survival rate of 10% was observed in the control group; in the case of SG9 challenge, the survival rate was 70% in the vaccinated group using the S06004ΔSPI2 mutant strain, compared with 0% in the control group vaccinated with PBS. The results indicated that S06004ΔSPI2 is a potential live attenuated vaccine to protect chickens against FT and PD. Despite the fact that the results of both studies are encouraging for continued research, LD50 or ID50 must be determined for the SP challenge strain and the S06004ΔSPI2 mutant strain following the recommendation of the OIE [40]. In all aforementioned studies, different SG and new SP vaccine candidates were developed, and a few of them have been used commercially to prevent and control FT in developing countries. The candidates have been tested under laboratory conditions using a few animals, and no replications were performed to demonstrate the consistency of the safety and efficacy results; additionally, the vaccine candidates have not been tested under field conditions. Interestingly, field vaccination programs for preventing and controlling SG used live attenuated and inactivated vaccines together. There is no scientific reason for using both vaccines, and this practice is related to immune concepts of protection based on serological responses, which are probably related to viral vaccines and immune response. Inactivated products fail to elicit a cell-mediated immune response and intestinal colonization [41], responsible for clearing intracellular facultative pathogens, express a limited number of antigens unlike attenuated strains [2], and neither stimulates SIgA responses at mucosal surfaces, the principal mechanism against intestinal colonization [15]. This concept cannot be applied for Salmonella live attenuated oral vaccines because of their mechanisms of action, which activate the mucosal and systemic immune response [2, 15, 42, 43], preventing the adhesion, the first step of Salmonella colonization, and stimulating mucosal and systemic Cell-mediated immune (CMI) responses. Salmonella Vaccines: Homologous or Heterologous Protection and Colonization-Inhibition Effect A holistic approach characterized by the comprehension of the different parts of a Salmonella control program, is the principal tool taking into account all variables involved in which vaccination is a small portion. Salmonella vaccination can be used as part of a comprehensive control and prevention program because a complete immune response is a complimentary tool for controlling Salmonella from infected birds. Live Salmonella vaccines induce better protection than killed vaccines [44], and oral live attenuated vaccines lead to the induction of a strong cellular immune response and mucosal immunity in vaccinated birds. When discussing homologous or heterologous protection, it is necessary to begin by including definitions of the 2 words from a scientific point of view: Homologous is a degree of similarity, as in position or structure, and it may indicate a common origin or a state of similarity in structure and anatomical position, but possibly not in function, between different organisms, suggesting a common ancestry or evolutionary origin. Heterologous means different origins, or the lack of correspondence of apparently similar organic structures as a result of unlike origins of constituent parts. From this point of view, homologous strains belong to the same O9 group of SG or SG biovar pullorum, and inside this group, we can have homologous isogenic strains when all individuals are genetically identical. Regarding homologous and heterologous protection, some work has been done with different approaches. In the 1990s, a study evaluated an experimental vaccination program using a live avirulent Salmonella Typhimurium (ST) strain to protect immunized chickens against challenge with homologous and heterologous Salmonella serovars belonging to different antigenic groups [45]. In this study, the results showed that homologous protection using the vaccine Δcya Δcrp ST was better than heterologous protection and that the protection conferred by the Δcya Δcrp vaccine was significantly different in vaccinated birds compared to unvaccinated chickens. The ST Δcya Δcrp live vaccine reported little effect on the transmission of Salmonella among SE, indicating that heterologous protection does not have good efficacy for protecting birds against Salmonella [46]. Similar results (indicating that cross protection to other antigenically similar serovars was not efficacious) have been published, which confirm that vaccine manufactured with a specific serovar can provide protection against serovars in the same group, but this protection was incomplete because antigenically unrelated Salmonella serovars were not covered by the vaccines [47]. Other studies have demonstrated that SE vaccines can provide homologous protection against Salmonella serovars of the same group, conferring efficacious cross protection against SG infections [35, 36]. Inoculation with attenuated ST vaccines resulted in a weak, but significantly reduced, colonization by ST, and colonization by SE could not be diminished by either of the ST vaccine strains [48]. Homologous protection was described in a trial using a live attenuated SE vaccine against FT in birds and showed good protection under laboratory experimental and field conditions [35, 36]. Recently, a study using a live attenuated ST that primed and boosted immunization by oral route was conducted to evaluate protection against SE, ST, and SG challenge strains, and the results showed that cross protection was significantly efficacious. In this study, SE and ST challenge strains were reduced in the liver, spleen, and cecal tissues in chickens vaccinated with the ST strain, and after SG challenge, mortality was reduced significantly in vaccinated birds. This study suggested that attenuated ST strains can confer protection against ST, SE, and SG infections [49], indicating heterologous protection of an ST strain. In this study, the SG challenge strain caused 55% mortality in unvaccinated birds, compared to 20% mortality in the vaccinated group; curiously, protection against a homologous challenge (ST strain) has higher bacterial recovery than a heterologous challenge with an SE strain 1, 4, and 7 d after challenge. Other studies suggested that dam mutant vaccines reduce Salmonella colonization and contamination caused by a number of heterologous serovars in the poultry industry [50, 51], and these results are similar to those of studies conducted in calves with a dam mutant ST strain that conferred cross protection against virulent Salmonella Newport [52]. In contrast, studies of cross-protective immunity in chickens demonstrated that expression of all interleukins (IL1β, IL17, IL22, and IFNγ), inducible NO synthase (iNOS), and extracellular fatty acid-binding protein (Ex-FABP) was significantly higher against homologous serovars than against heterologous serovars [53]. On the other hand, priming with either ST or SE activates strong cross-reactive protection and considerable protection to challenge with either serovar, suggesting the conservation of protective antigens; SE (O9) or ST (O4) vaccines could provide heterologous protection against serovars belonging to the same or different groups [54]. Evidence in the field in developing countries indicates that this protection may be variable and almost always involves partial or very limited protection against cecal colonization, organ invasion (spleen, liver, ovaries), and fecal excretion. Despite the fact that SG and SP poorly colonize the intestine [55], it was demonstrated that SPI-19 (Salmonella Pathogenicity Island 19) and T6SS (Type VI Secretion System), which are encoded in this region, contribute to colonization of the gastrointestinal tract by SG [56]. The colonization-inhibition effect of the SG vaccines can be exploited based on fecal-oral [47] or respiratory transmission [57] of the bacteria. This recent work suggests a colonization-inhibition concept in which a live Salmonella strain orally administered to day-old chickens can potentially be used as a control method of FT. For the exploitation of this phenomenon in live attenuated SG vaccines for poultry, information on colonization inhibition between wild-type strains of Salmonella enterica subsp. enterica within the same and different serovars is needed [58]. Salmonella strains were shown to inhibit colonization by other Salmonella strains to varying degrees [59]. Moreover, besides stimulating the development of true immunity to the infection, the oral administration of live Salmonella vaccines to day-old chicks also induced a colonization-inhibition effect against other Salmonella strains within a short period of time. Evidence on the specificity of inhibition between Salmonella strains is provided by the facts that a) the best inhibition is produced between isogenic Salmonella strains; b) inhibition between strains of the same serovar is much more effective than between strains of different serovars; and c) the inhibitory effect does not occur between unrelated organisms [60]. The colonization-inhibition effect was tested in vivo [55] between single and mixed strains belonging to the serogroups O4 (former group B), O9 (former group B), O6, O7, and O8 (former group C), and O13 (former group G) in young chickens. The results of the trial showed that the colonization-inhibition effect was the strongest between isogenic strains (strains of the same clone) and that the inhibition effect between SE strains was considerably greater than the effect between ST strains. Almost no inhibitory effect was produced by the rough strain of ST 1464, and none of the ST strains was able to reduce the intestinal growth of the heterologous strain of SE 147NA. SE strain phage type 4 showed very high inhibition against non-isogenic strains, and in some cases, it showed nearly complete inhibition against non-isogenic strains. None of the SE strains was able to influence the cecal colonization of the heterologous strain ST 9098NA. The colonization-inhibition effect is more pronounced between isogenic strains, and there is greater inhibition within a serovar than between serovars [58, 60, 61]. Therefore, protection conferred by oral vaccination with live homologous salmonellae has been shown to induce protection against visceral invasion by the challenge strain with a reduction in the colonization of the gastrointestinal tract [62, 63, 64]. A Regulatory and Practical Overview of FT and PD Vaccines in Developing Countries It is important to remember that there is no inactivated or live attenuated vaccine against SG that is capable of protecting birds against high levels of challenge and that vaccination is a very small part of a control program; however, vaccination is very good tool if production management conditions are efficiently conducted. If there is a safe and efficacious vaccine for controlling FT or PD outbreaks with negligible risk, the challenge of vaccine manufacturers is to perform studies to demonstrate results to enable new vaccination strategies for managing both diseases in developing countries. These studies can support new proposals aimed to reach excellence in controlling host-specific salmonellosis. Currently, the use of SG9R is allowed in some Latin American countries [35], but there are no technical guidelines for testing SG vaccines from a regulatory point of view. The criteria for an ideal Salmonella vaccine have been described extensively, and they include wide protection, attenuation, reduction of intestinal colonization, compatibility with other control measures, cost effective application, and long-lasting protection; in few words, Salmonella strategy should represent a holistic approach for preventing and controlling FT and PD [65]. Interestingly, because of the eradication programs in different regions of the world, live attenuated vaccines to control systemic salmonellosis in poultry do not have any specific guides like monographs in the Pharmacopoeias or other regulations [66, 67]. It would be useful and practical for authorities and manufacturers in developing countries to develop a guideline including all parameters and tests that are necessary for licensing a live attenuated vaccine against FT or PD. Some of the aspects that should be considered are reduced excretion, ability to persist in an environment of vaccinated birds, absence of transmission to eggs, clearance of wild SG from vaccinated birds, safe use during the laying period, no residual virulence, suitable efficacy, and protection of vaccinated birds. A vaccine withdrawal period before slaughter in domestic birds raised for meat or eggs should be required in relevant studies. Standardization guidelines are important because FT and PD vaccines must follow the same rules as those of other Salmonella vaccines. Furthermore, because of FT and PD continue to be a problem in poultry production in Africa, Asia, and Latin America, guidelines are required to guarantee safe and efficacious products. Rules should be similar to those described in 9 CFR 113.100 113.120, 113.122, and 113.123 for inactivated Salmonella vaccines in the United States [66] or as recommended by the European Pharmacopoeia monographs 1947 and 2361 for inactivated SE and ST vaccines or 2520 and 2521 for SE and ST live attenuated vaccines for chickens [67]. From a regulatory point of view, having defined guidelines for vaccines intended for active immunization against SG manufactured from SG strains would help manufacturers and authorities in strain selection and development and in assessing products based on a reference standard, respectively. For example, challenge trials must require DL50, taking into account that in vivo passages can increase the virulence of the SG strain [68]. Some topics for a guideline for SG and SP vaccines are proposed in Table 2. Table 2. Proposed master seed and finished product requirements applicable to vaccines manufactured using SG or SP strains. Topics Information/tests required Selection Strain must have satisfactory safety and efficacy Strain should have a stable marker or suitable identification to differentiate it from wild SG or SP strains DL50 compared to parent/pathogenic strain Development Records of origin, date of isolation, passage, and propagation history Preparation of media, seed cultures, inoculation, incubation, fermentation, titration, and other related materials and methods must be documented Maximum bacterial count regarding safety must be determined Propagation harvest and bulk Identity and purity Morphology and biochemical, serological, and antimicrobial susceptibility All applicable molecular techniques to determine the profile and strain characteristics A suitable method to determine the purity of the master seed must be described Master seed Safety Minimum age of chickens for testing safety, minimum number of chickens, maximum bacterial content applied, observation period Minimum age for vaccination Excretion assessed by reisolation in cloacal and environmental swabs tested weekly in vaccinated and contact chickens Spread assessed by organ culture of liver, spleen, oviduct/ovaries, and cecal content in vaccinated and contact birds Passage in chickens at least 5 times to verify increase of virulence Test must be performed in chickens for breeding/laying of meat production accordingly Immunogenicity Mortality must be reduced in target species/category of birds (P < 0.05) Isolation of challenge strain from organs of vaccinated birds is reduced significantly (P < 0.05) compared to the control group (unvaccinated and challenged) Finished product Identity Bacterial morphology, biochemical, and serological methods, culture, PCR, or other molecular methods Sterility Absence of bacteria and fungi Titration (potency) CFU/dose (bacterial count at release) Storage Stability data at the end of the shelf-life period, for freeze-dried products residual moisture must be included. Storage temperature and shelf life based on stability data must be included. Topics Information/tests required Selection Strain must have satisfactory safety and efficacy Strain should have a stable marker or suitable identification to differentiate it from wild SG or SP strains DL50 compared to parent/pathogenic strain Development Records of origin, date of isolation, passage, and propagation history Preparation of media, seed cultures, inoculation, incubation, fermentation, titration, and other related materials and methods must be documented Maximum bacterial count regarding safety must be determined Propagation harvest and bulk Identity and purity Morphology and biochemical, serological, and antimicrobial susceptibility All applicable molecular techniques to determine the profile and strain characteristics A suitable method to determine the purity of the master seed must be described Master seed Safety Minimum age of chickens for testing safety, minimum number of chickens, maximum bacterial content applied, observation period Minimum age for vaccination Excretion assessed by reisolation in cloacal and environmental swabs tested weekly in vaccinated and contact chickens Spread assessed by organ culture of liver, spleen, oviduct/ovaries, and cecal content in vaccinated and contact birds Passage in chickens at least 5 times to verify increase of virulence Test must be performed in chickens for breeding/laying of meat production accordingly Immunogenicity Mortality must be reduced in target species/category of birds (P < 0.05) Isolation of challenge strain from organs of vaccinated birds is reduced significantly (P < 0.05) compared to the control group (unvaccinated and challenged) Finished product Identity Bacterial morphology, biochemical, and serological methods, culture, PCR, or other molecular methods Sterility Absence of bacteria and fungi Titration (potency) CFU/dose (bacterial count at release) Storage Stability data at the end of the shelf-life period, for freeze-dried products residual moisture must be included. Storage temperature and shelf life based on stability data must be included. View Large Table 2. Proposed master seed and finished product requirements applicable to vaccines manufactured using SG or SP strains. Topics Information/tests required Selection Strain must have satisfactory safety and efficacy Strain should have a stable marker or suitable identification to differentiate it from wild SG or SP strains DL50 compared to parent/pathogenic strain Development Records of origin, date of isolation, passage, and propagation history Preparation of media, seed cultures, inoculation, incubation, fermentation, titration, and other related materials and methods must be documented Maximum bacterial count regarding safety must be determined Propagation harvest and bulk Identity and purity Morphology and biochemical, serological, and antimicrobial susceptibility All applicable molecular techniques to determine the profile and strain characteristics A suitable method to determine the purity of the master seed must be described Master seed Safety Minimum age of chickens for testing safety, minimum number of chickens, maximum bacterial content applied, observation period Minimum age for vaccination Excretion assessed by reisolation in cloacal and environmental swabs tested weekly in vaccinated and contact chickens Spread assessed by organ culture of liver, spleen, oviduct/ovaries, and cecal content in vaccinated and contact birds Passage in chickens at least 5 times to verify increase of virulence Test must be performed in chickens for breeding/laying of meat production accordingly Immunogenicity Mortality must be reduced in target species/category of birds (P < 0.05) Isolation of challenge strain from organs of vaccinated birds is reduced significantly (P < 0.05) compared to the control group (unvaccinated and challenged) Finished product Identity Bacterial morphology, biochemical, and serological methods, culture, PCR, or other molecular methods Sterility Absence of bacteria and fungi Titration (potency) CFU/dose (bacterial count at release) Storage Stability data at the end of the shelf-life period, for freeze-dried products residual moisture must be included. Storage temperature and shelf life based on stability data must be included. Topics Information/tests required Selection Strain must have satisfactory safety and efficacy Strain should have a stable marker or suitable identification to differentiate it from wild SG or SP strains DL50 compared to parent/pathogenic strain Development Records of origin, date of isolation, passage, and propagation history Preparation of media, seed cultures, inoculation, incubation, fermentation, titration, and other related materials and methods must be documented Maximum bacterial count regarding safety must be determined Propagation harvest and bulk Identity and purity Morphology and biochemical, serological, and antimicrobial susceptibility All applicable molecular techniques to determine the profile and strain characteristics A suitable method to determine the purity of the master seed must be described Master seed Safety Minimum age of chickens for testing safety, minimum number of chickens, maximum bacterial content applied, observation period Minimum age for vaccination Excretion assessed by reisolation in cloacal and environmental swabs tested weekly in vaccinated and contact chickens Spread assessed by organ culture of liver, spleen, oviduct/ovaries, and cecal content in vaccinated and contact birds Passage in chickens at least 5 times to verify increase of virulence Test must be performed in chickens for breeding/laying of meat production accordingly Immunogenicity Mortality must be reduced in target species/category of birds (P < 0.05) Isolation of challenge strain from organs of vaccinated birds is reduced significantly (P < 0.05) compared to the control group (unvaccinated and challenged) Finished product Identity Bacterial morphology, biochemical, and serological methods, culture, PCR, or other molecular methods Sterility Absence of bacteria and fungi Titration (potency) CFU/dose (bacterial count at release) Storage Stability data at the end of the shelf-life period, for freeze-dried products residual moisture must be included. Storage temperature and shelf life based on stability data must be included. View Large Unfortunately, most developing countries have developed FT and PD programs by copying successful programs in other regions of the world; however, these programs have not been adjusted based on epidemiological knowledge and updated data on disease situations; also, as mentioned in the sections above, underreporting of outbreaks occurs because of regulatory authority restrictions and the absence of coordination between sanitary official authorities and the poultry industry. As a result, the occurrence of diseases such as FT and PD is unknown, and programs are not based on real information. Consequently, the eradication programs established in most developing countries are impractical because costs have never been assessed. A holistic approach is indispensable to controlling FT and PD in developing countries; the principle of eradication should be reviewed and changed by control programs focused on strategies that consider the coexistence of poultry production and the agents of FT and PD. Based on this analysis, developing countries should apply “therapeutic vaccination,” a concept that means the ability of a vaccine strain to clear the SG or SP bacteria from infected birds, to clear infected cells and prevent colonization and organ invasion after field challenge. This concept could be applied for an ideal SG vaccine, and the poultry industry, vaccine manufacturers, and authorities should work together to control FT and PD in developing countries. FINANCIAL AND COMPETING INTEREST DISCLOSURE L. Revolledo is an independent consultant for the poultry industry in Latin America. The author has no relevant affiliation or financial involvement with any company, organization, or entity with a financial interest in or a financial conflict with the subject matter or materials discussed in this review. CONCLUSIONS AND APPLICATIONS Most developing countries have established eradication or control programs for FT and PD based on theoretical data due to the absence of real information and underreporting of FT and PD outbreaks. Killed vaccines against SG do not elicit a cell-mediated immune response, which is indispensable for clearing the bacteria. Live attenuated vaccines against SG based on the 9R strain have shown good results, but they can be replaced by new products that are the result of newly developed technologies, avoiding the possibility of reversion to a more virulent phenotype demonstrated by gene mutations aceE and rfsj. Live attenuated vaccines based on an SE drift mutant attenuated strain have demonstrated cross protection against FT and have shown clearance of the challenge strain from infected birds; they are an excellent tool for strategies based on “therapeutic vaccination” in developing countries according to the epidemiological situation in the region. Salmonella vaccines have demonstrated protection against Salmonella serovars in the same group, showing that homologous serovars can have efficacious cross protection. Standard guidelines for manufacturing vaccines containing live SG strain are required, and they should be similar to the international rules contained in the European Pharmacopoeia in the European Union or the Code of Federal Regulations in the United States for vaccines manufactured with host-specific Salmonella or non-hot specific Salmonella. 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Vaccines and vaccination against fowl typhoid and pullorum disease: An overview and approaches in developing countries

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Applied Poultry Science, Inc.
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© 2018 Poultry Science Association Inc.
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1056-6171
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1537-0437
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10.3382/japr/pfx066
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Abstract

SUMMARY In poultry, host-specific Salmonella infections cause fowl typhoid and pullorum disease, which are severe systemic diseases of chickens that result in severe problems and high mortality and produce economic losses in developing countries. Fowl typhoid and pullorum disease have reemerged in recent years in developing countries, and birds of any age can be infected. Developing countries have established sanitary measures and official programs to prevent and control both diseases; however, there are cyclic or seasonal outbreaks related to disease management. An overview of the current situation and future perspectives regarding live attenuated vaccines against fowl typhoid and pullorum disease are discussed. Fowl Typhoid and Pullorum Disease Situation in Developing Countries Host-specific Salmonella infections cause fowl typhoid (FT) and pullorum disease (PD) in poultry, but are avirulent in mammals. These diseases are distributed worldwide [1] and have been eradicated in many developed countries [2]; however, they remain responsible for economic losses in the poultry industry in developing countries in Africa, Asia and Latin America [3]. Although many developed countries have successfully eradicated host-specific Salmonella (FT and PD) via testing and slaughtering at infected farms, the scenario is different in developing countries, where eradication is not realistic and may not be an option. There are many differences between developing and developed countries. First, sanitary programs for controlling FT and PD are different in developing countries, and information regarding the incidence or prevalence of infections is lacking. Most developing countries use passive surveillance, collecting data from different sources, but underreporting is a big problem with this strategy. Few developing countries have active surveillance for Salmonella Gallinarum (SG) and Salmonella Pullorum (SP) as part of their national monitoring programs for poultry diseases. Therefore, the official data submitted to OIE (World Animal Health Organization) do not always reflect what occurs in the field. Based on 2005 to 2015 data from the OIE database [4] recovered from with WAHIS Interface and OIE notification procedure [5] FT was never reported in 2 countries, and 4 countries had no information on this disease. The disease was present in 22 territories out of 59 reporting countries in Africa. The Americas region included 52 reporting territories, but 14 territories did not have any kind of available information; FT was never reported in 11 territories, was absent in 14 territories, and was present in only 9 countries. In Asia (46 reporting territories), FT was never reported in 5 countries, and 2 territories did not show any information; FT was present in 14 territories and absent in 32 territories. In Oceania (31 reporting territories), 20 territories did not have information, and FT was never reported in 6 territories. In Europe (53 reporting territories), 5 countries never reported FT during 2005 to 2015, and there were no countries without any kind of information. Regarding PD, only one country in Africa (59 territories) never reported the disease. In the Americas (52 reporting territories), 11 never reported PD, and there was no information available from 17 countries. In Asia (46 reporting territories), one country never reported PD, and 4 countries did not have any kind of available information. In Europe (54 reporting territories), 3 countries never reported the disease, and there was no available information for 2 countries. Consequently, data available on outbreaks in developing countries from official sources suggest that these diseases are underreported [6]. This situation is exacerbated in developing countries by a lack of active surveillance in commercial flocks and a lack of monitoring or surveillance for ornamental, hobby, backyard, game, or wildlife birds, which can remain a constant reservoir of SP and SG. Furthermore, these non-commercial bird species are not included in national poultry programs, except for avian influenza in some countries. The second situation is related to managing the control of FT and PD caused by SP and SG and the use of antimicrobial therapy against both diseases. It is important to note that antimicrobial therapy is still being used for FT and PD [6] at the farm level as an alternative means of reducing mortality; however, antibiotic therapy does not clear the infection from a flock. The administration of antimicrobials at low doses for extended durations for growth promotion and disease prevention has been linked to the global crisis of antimicrobial resistance [7]. Interestingly, despite scientific evidence that antimicrobials do not clear Salmonella infections and that they can be responsible for carriers, antimicrobial resistance, and residues in egg production [8], antimicrobial products continue to be used to reduce flock mortality in developing countries. Recent investigations using fluoroquinolones in a controlled experimental model in Brazil [9] confirmed that chemotherapy during outbreaks facilitates the persistence of SG in poultry. The worst effect of therapeutic treatments and dosage is the use of different kinds of antimicrobial products, or mixtures of more than one active ingredient, based only on clinical evidence without strain isolation or knowledge of pharmacological properties, Minimum inhibitory concentration (MIC) measurements, or susceptibility tests of isolates. Consequently, antimicrobial-resistant strains have appeared, and multidrug-resistant (MDR) isolates of SP have been reported [10]. MDR strains have been a major impediment in the treatment of FT using antimicrobials [3, 11]. A second challenge relates to scientific evidence that host stress drives Salmonella recrudescence associated with neuroendocrine responses and the direct effect of stress mediators on bacteria and gene expression, driven by the scsA gene to respond to the host stress hormone cortisol inducing the macrophage cytoskeletal rearrangements that facilitate intracellular bacterial replication [10, 11, 12]; thus, Salmonella can respond to subtherapeutic pressure by increasing its virulence and disease severity [13]. The third situation has a legal and economical basis. Developing countries have programs for controlling, preventing, and eradicating FT and PD, but the legal framework is not updated according to new approaches, the epidemiological situation, or new tools for diagnosis or prevention. Some local regulations permit vaccination using inactivated vaccines against Salmonella. These products were useful for many years, but live Salmonella vaccines based on the 9R strain (introduced in the 1950s) later appeared and were used in some countries. Attenuated Salmonella Enteritidis (SE) vaccines (introduced in the 1990s) with demonstrated efficacy to prevent and control SE and effective cross protection against SG infection were also introduced. On the other hand, eradication programs in developing countries do not include economic compensation for poultry producers. Vaccines and Vaccination for Controlling Fowl Typhoid and Pullorum Disease in Poultry There is ongoing interest in finding ways to prevent and control flock infection, and hence, vertical and horizontal transmission. Vaccination has been the most practical and effective strategy for controlling FT in developing countries where SG is endemic [14], and new attenuated strains are being investigated. Inactivated products are killed bacteria, using different adjuvants to improve their immunogenic properties, and these products have been used to protect poultry and their progeny against field challenges; however, they do not elicit a cell-mediated immune response, which is indispensable for the clearance of Salmonella [15]. They increase circulating antibodies, reducing Salmonella in the external milieu and decreasing excretion in feces. A group of experimental products called bacterial ghosts is an innovative approach to non-living vaccine technology that can aid FT control programs. These ghosts are believed to maintain all functional and antigenic structures in the envelope, including bioadhesive properties and the capability to induce a complete immune response [16]. Regarding this new candidate, an efficacy study showed that mortality was controlled more efficiently in the group vaccinated intramuscularly than in the unvaccinated and orally vaccinated groups. The development of a cell-mediated immune response after vaccination was demonstrated, and challenge results were evaluated using mortality and gross lesions scores [17]; however, there were no assessments of challenge strain persistence in cecal content, liver, or spleen in vaccinated and challenged birds, so further studies are needed. Live attenuated vaccines were first developed to prevent FT in 1956, which is when the SG rough strain was developed [18]; however, the vaccine should be avoided because the nature of its attenuation is not known [19, 20]. The SG 9R (SG9R) vaccine strain still results in systemic disease, and it was suggested that variants can cause some outbreaks, indicating that gene mutations aceE and rfsj could explain the reversion to a more virulent phenotype [21]. The use of SG9R in poultry outbreaks in the field in clinically healthy birds has a high frequency of increasing the virulence of the SG9R strain, which might be explained by the interaction among the circulating strain, the vaccine strain, and the host; certain environmental conditions also may be involved in the reversion of the virulence of the vaccine strain. Later, many attempts to prevent FT by vaccination with SG strains were developed; some mutant strains were tested (Table 1), but they are not commercially available, except for the SG9R strain. As a safe alternative, an attenuated live vaccine containing a metabolic drift mutant strain of SE was used with success against FT in layers [35, 36]. Table 1. Live attenuated mutant strains for controlling fowl typhoid. Salmonella serotype Mutant strain/attenuation Advantages Disadvantages aroA mutant [20] Highly attenuated for chickens Poor protection after intramuscular administration, no protection after oral administration aroA-serC mutant [22] Highly attenuated, 100% protection in 106 challenge Intramuscular administration cobS and cbiA mutant [23, 24] Oral vaccination, reduced mortality in brown chickens after SG challenge Lesions in organs can be observed, one vaccination did not affect shedding of an SE challenge, vaccination does not prevent cecal colonization of SE challenge strain crp mutant [25] Suggested protective ability fur mutant [14] Avirulent in chicks, excellent protection when given orally to Rhode Island Red chickens Not effective when given orally to older birds Salmonella Gallinarum lon cpxR mutant [26] Double mutant, no mortality after challenge Egg contamination and persistence were not evaluated, safety concern lon cpxR asd mutant [27] Induced acquired immunity and protected birds after challenge, gross lesions in spleen and liver 3 d post inoculation, safer than lon cpxR mutant and SG9R Intramuscular administration, mucosal immunity was not evaluated SG metabolic drift mutant [28] Double marker demonstrated no differences compared with the control group, vaccinated chickens were protected against challenge Single marker showed residual gross lesions in liver or spleen, OD readings in serum samples of IgG was observed 15 d post vaccination, Rif1-Sm10 strain does not show protection against challenge metC mutant [29] No mortality or clinical signs Further investigation of efficacy of metC mutant as potential genetically engineered live vaccine candidate nuoG mutant [30] Highly attenuated Poor protection, high persistence, less invasive Semi-rough lipopolysaccharide structure (9R strain) [18, 19, 21] Reduced mortality Undefined mutation, residual virulence speB speE mutant [31] Polyamine biosynthesis is essential for oral infection of SG Virulence restored by reintroducing speB gene on a plasmid E-lysis system [32] Safe for chickens Subcutaneous administration, reduction of mortality after 2 vaccinations, inactivated product rpoS, hmp and ssrAB triple-deletion mutant [33] Complete protection against challenge with wild-type SG, no mortality in birds inoculated with 108 CFU Vaccine strain isolation in liver and spleen were higher than levels with vaccination using SG9R sipC srp deletion mutant [34] Protective efficacy against mortality Intramuscular vaccination Salmonella Enteritidis Metabolic drift mutant [35, 36] Oral administration, effective in presence of maternal antibodies, prevented SE infections, clearance of SG from the host, environmental safety Cannot be applied with anticoccidial vaccines Salmonella serotype Mutant strain/attenuation Advantages Disadvantages aroA mutant [20] Highly attenuated for chickens Poor protection after intramuscular administration, no protection after oral administration aroA-serC mutant [22] Highly attenuated, 100% protection in 106 challenge Intramuscular administration cobS and cbiA mutant [23, 24] Oral vaccination, reduced mortality in brown chickens after SG challenge Lesions in organs can be observed, one vaccination did not affect shedding of an SE challenge, vaccination does not prevent cecal colonization of SE challenge strain crp mutant [25] Suggested protective ability fur mutant [14] Avirulent in chicks, excellent protection when given orally to Rhode Island Red chickens Not effective when given orally to older birds Salmonella Gallinarum lon cpxR mutant [26] Double mutant, no mortality after challenge Egg contamination and persistence were not evaluated, safety concern lon cpxR asd mutant [27] Induced acquired immunity and protected birds after challenge, gross lesions in spleen and liver 3 d post inoculation, safer than lon cpxR mutant and SG9R Intramuscular administration, mucosal immunity was not evaluated SG metabolic drift mutant [28] Double marker demonstrated no differences compared with the control group, vaccinated chickens were protected against challenge Single marker showed residual gross lesions in liver or spleen, OD readings in serum samples of IgG was observed 15 d post vaccination, Rif1-Sm10 strain does not show protection against challenge metC mutant [29] No mortality or clinical signs Further investigation of efficacy of metC mutant as potential genetically engineered live vaccine candidate nuoG mutant [30] Highly attenuated Poor protection, high persistence, less invasive Semi-rough lipopolysaccharide structure (9R strain) [18, 19, 21] Reduced mortality Undefined mutation, residual virulence speB speE mutant [31] Polyamine biosynthesis is essential for oral infection of SG Virulence restored by reintroducing speB gene on a plasmid E-lysis system [32] Safe for chickens Subcutaneous administration, reduction of mortality after 2 vaccinations, inactivated product rpoS, hmp and ssrAB triple-deletion mutant [33] Complete protection against challenge with wild-type SG, no mortality in birds inoculated with 108 CFU Vaccine strain isolation in liver and spleen were higher than levels with vaccination using SG9R sipC srp deletion mutant [34] Protective efficacy against mortality Intramuscular vaccination Salmonella Enteritidis Metabolic drift mutant [35, 36] Oral administration, effective in presence of maternal antibodies, prevented SE infections, clearance of SG from the host, environmental safety Cannot be applied with anticoccidial vaccines View Large Table 1. Live attenuated mutant strains for controlling fowl typhoid. Salmonella serotype Mutant strain/attenuation Advantages Disadvantages aroA mutant [20] Highly attenuated for chickens Poor protection after intramuscular administration, no protection after oral administration aroA-serC mutant [22] Highly attenuated, 100% protection in 106 challenge Intramuscular administration cobS and cbiA mutant [23, 24] Oral vaccination, reduced mortality in brown chickens after SG challenge Lesions in organs can be observed, one vaccination did not affect shedding of an SE challenge, vaccination does not prevent cecal colonization of SE challenge strain crp mutant [25] Suggested protective ability fur mutant [14] Avirulent in chicks, excellent protection when given orally to Rhode Island Red chickens Not effective when given orally to older birds Salmonella Gallinarum lon cpxR mutant [26] Double mutant, no mortality after challenge Egg contamination and persistence were not evaluated, safety concern lon cpxR asd mutant [27] Induced acquired immunity and protected birds after challenge, gross lesions in spleen and liver 3 d post inoculation, safer than lon cpxR mutant and SG9R Intramuscular administration, mucosal immunity was not evaluated SG metabolic drift mutant [28] Double marker demonstrated no differences compared with the control group, vaccinated chickens were protected against challenge Single marker showed residual gross lesions in liver or spleen, OD readings in serum samples of IgG was observed 15 d post vaccination, Rif1-Sm10 strain does not show protection against challenge metC mutant [29] No mortality or clinical signs Further investigation of efficacy of metC mutant as potential genetically engineered live vaccine candidate nuoG mutant [30] Highly attenuated Poor protection, high persistence, less invasive Semi-rough lipopolysaccharide structure (9R strain) [18, 19, 21] Reduced mortality Undefined mutation, residual virulence speB speE mutant [31] Polyamine biosynthesis is essential for oral infection of SG Virulence restored by reintroducing speB gene on a plasmid E-lysis system [32] Safe for chickens Subcutaneous administration, reduction of mortality after 2 vaccinations, inactivated product rpoS, hmp and ssrAB triple-deletion mutant [33] Complete protection against challenge with wild-type SG, no mortality in birds inoculated with 108 CFU Vaccine strain isolation in liver and spleen were higher than levels with vaccination using SG9R sipC srp deletion mutant [34] Protective efficacy against mortality Intramuscular vaccination Salmonella Enteritidis Metabolic drift mutant [35, 36] Oral administration, effective in presence of maternal antibodies, prevented SE infections, clearance of SG from the host, environmental safety Cannot be applied with anticoccidial vaccines Salmonella serotype Mutant strain/attenuation Advantages Disadvantages aroA mutant [20] Highly attenuated for chickens Poor protection after intramuscular administration, no protection after oral administration aroA-serC mutant [22] Highly attenuated, 100% protection in 106 challenge Intramuscular administration cobS and cbiA mutant [23, 24] Oral vaccination, reduced mortality in brown chickens after SG challenge Lesions in organs can be observed, one vaccination did not affect shedding of an SE challenge, vaccination does not prevent cecal colonization of SE challenge strain crp mutant [25] Suggested protective ability fur mutant [14] Avirulent in chicks, excellent protection when given orally to Rhode Island Red chickens Not effective when given orally to older birds Salmonella Gallinarum lon cpxR mutant [26] Double mutant, no mortality after challenge Egg contamination and persistence were not evaluated, safety concern lon cpxR asd mutant [27] Induced acquired immunity and protected birds after challenge, gross lesions in spleen and liver 3 d post inoculation, safer than lon cpxR mutant and SG9R Intramuscular administration, mucosal immunity was not evaluated SG metabolic drift mutant [28] Double marker demonstrated no differences compared with the control group, vaccinated chickens were protected against challenge Single marker showed residual gross lesions in liver or spleen, OD readings in serum samples of IgG was observed 15 d post vaccination, Rif1-Sm10 strain does not show protection against challenge metC mutant [29] No mortality or clinical signs Further investigation of efficacy of metC mutant as potential genetically engineered live vaccine candidate nuoG mutant [30] Highly attenuated Poor protection, high persistence, less invasive Semi-rough lipopolysaccharide structure (9R strain) [18, 19, 21] Reduced mortality Undefined mutation, residual virulence speB speE mutant [31] Polyamine biosynthesis is essential for oral infection of SG Virulence restored by reintroducing speB gene on a plasmid E-lysis system [32] Safe for chickens Subcutaneous administration, reduction of mortality after 2 vaccinations, inactivated product rpoS, hmp and ssrAB triple-deletion mutant [33] Complete protection against challenge with wild-type SG, no mortality in birds inoculated with 108 CFU Vaccine strain isolation in liver and spleen were higher than levels with vaccination using SG9R sipC srp deletion mutant [34] Protective efficacy against mortality Intramuscular vaccination Salmonella Enteritidis Metabolic drift mutant [35, 36] Oral administration, effective in presence of maternal antibodies, prevented SE infections, clearance of SG from the host, environmental safety Cannot be applied with anticoccidial vaccines View Large Two experimental vaccines were developed in the 1990s, but they had poor protection and environmental persistence. First, an aroA mutant of SG was tested, and it was shown to be highly attenuated when inoculated orally and intramuscularly. It persisted in different tissues for no more than 9 d, but the protection in birds was poor compared to that of the SG9R strain, so it was not useful for protecting chickens [20]. The second vaccine was a nuoG mutation introduced into a virulent SG strain [30]; its protection was similar to or better than that of SG9R, and the degree of invasiveness in the intestine, liver, and spleen was reduced compared to that in the wild-type strain. However, the vaccine strain persisted for at least 6 weeks. Two yr later, in 2000, an aromatic dependent mutant of a wild-type SG strain that was lysogenic for P22 sie was developed, and it was the first report of attenuation associated with lysogenization. The SL5828 strain was administered intramuscularly and had excellent results in immune protection studies, conferring 100% protection against the homologous strain [22]. In 2007, a metC mutant of SG was constructed, and various experiments were carried out to assess the effects of this mutation on virulence and invasiveness. This study suggested that the metC mutant of SG could be a potential genetically engineered vaccine candidate against FT [29]. Another mutant of SG was developed and evaluated in Brazil [23, 24] with deletions in genes cobS and cbiA, which are involved in the biosynthesis of cobalamin, and this mutant strain was tested for efficacy in 2 experiments performed separately. This mutant strain was administered once or twice and showed efficacy in brown chickens against mortality caused by a SG wild-type challenge, whereas its efficacy in white chickens was demonstrated after one or 2 vaccinations. This experimental vaccine strain administered once at 5 d of age in brown chickens conferred 85% protection against mortality caused by a homologous wild-type strain challenge compared to the unvaccinated and challenged group, and 75% protection when administered twice (at 5 and 25 d of age). This ΔcobSΔcbiA strain induces a systemic response of IgY, suggesting that Th1 and Th2 responses are produced in vaccinated birds [24]. The safety and efficacy of another double mutant strain (lon/cpxR) was compared with SG9R in 6-week-old hens [26], and it showed that the vaccine was safe and had more efficient protection than SG9R with significantly decreased lesions in organs and recovery of the challenge strain. The efficacy of a live attenuated SG vaccine strain with deletion of the global regulatory gene fur was evaluated in Rhode Island Red chicks and brown leghorn layers [14]. The ferric uptake regulator (fur) protein acts as a repressor of many genes and is essential for the virulence of SG; fur deletion resulted in a complete attenuation of SG that was as effective as a live recombinant vaccine against FT influenced by the administration route. This vaccine protected Rhode Island Red chickens when it was administered orally in young chickens or intramuscularly in brown leghorn chickens [14]. A new vaccine candidate that secretes heat-labile enterotoxin B subunit protein was evaluated for safety, immunogenicity, and protective efficacy against FT in 2014 [27]. The live attenuated vaccine against SG, identified as JOL1355, was administered intramuscularly; it was safe, displayed no adverse effects in vaccinated chickens, and exhibited bacterial persistence in the spleen for 7 d post inoculation and small gross lesions up to 3 d post inoculation [27]. The vaccine strain had a positive effect on the complete clearance of the challenge wild-type SG strain from internal organs observed 14 d post inoculation; thus, this vaccine could be an excellent tool to induce acquired immunity and clear bacteria from infected birds. In 2014 [31], another SG strain was evaluated to explore whether polyamines are essential to the virulence of SG, and these results showed new ways for developing treatments for FT to inhibit these enzymes. A novel approach was developed to generate SG ghosts and assess their vaccine potential using a prime-booster vaccination [32]; however, inactivated vaccine administration can be a disadvantage compared to other available SG oral live attenuated vaccines. Live attenuated metabolic drift mutants of SG vaccines with a single or double attenuating marker have been tested, and they showed homologous protection and clearance of wild-type SG 14 d post challenge, which can be attributed to the clearance of the challenge strain by cellular mediated immunity. Mutants with 2 attenuating markers assure safety, and the probability of back mutation can almost be excluded [28]. A triple-deletion mutant was tested as a live vaccine candidate in Lohmann layer chickens; the results showed that the SGΔ3 mutant conferred complete protection against challenge with virulent SG [35], indicating that this strain could be a promising candidate for a live attenuated vaccine against FT. The triple mutant was used orally or subcutaneously, and the results indicated that the strain conferred a level of protection similar to SG9R; however, bacterial counts were higher than those in SG9R in the liver and spleen. Finally, a live attenuated SG spiC and crp deletion mutant was tested, and efficient protection was observed based on mortality and clinical symptoms [34]. On the other hand, there is a metabolic drift mutant strain of SE that has demonstrated efficacy against FT in some African and Latin American countries. The vaccine must be administered by drinking water 3 times. The vaccine strain was tested in layers using different vaccination schedules, and it was demonstrated that the SE metabolic drift mutant strain contained in the vaccine was able to protect hens against a SG challenge [35]. The vaccine was safe, it persisted in the environment for 12 d after first vaccination, and booster applications reduced excretion of the vaccine strain. Other studies on the efficacy of this vaccine were carried out in Morocco against SG infection [36], confirming the cross protection against FT in layers under controlled and field conditions. In contrast to the studies performed in Argentina [35], the vaccine strain was never re-isolated after vaccination in the environment or from internal organs [36]. There was a reduction of mortality in birds challenged at 20 wk (7.5% mortality in the vaccinated group), and the mortality was only 7.69% in birds challenged at 32 wk of age [36]. The most important assessment of the Moroccan study was the clearance of the challenge strain, and survivors of the SE metabolic drift mutant live vaccine cleared the SG challenge strain by 86.5% at the 23rd wk and 89% at the 34th wk challenge compared to the control group, which had an average of 6% for unvaccinated groups. Unpublished field experiences in Latin America by the author demonstrated that vaccination is efficacious during FT outbreaks, reducing mortality and clearing the bacteria from affected birds, when it is administered in poultry houses with good farming practices. It is important to note that vaccination efficacy is directly related to biosecurity measures, sanitation, and hygienic conditions. Vaccines against PD were not developed until this century. A sipC mutant has been described as a potential new vaccine candidate for use in chickens against PD [37] because the mutant strain (spiC::km) was attenuated and highly immunogenic compared to the parent strain, did not induce clinical signs for 4 wk, and was not isolated from organs beyond 8 d post infection. In 2015 [38], SPI-2 (Salmonella pathogenicity island 2) mutant of SP (S06004ΔSPI2) was tested for efficacy on 2-day-old chickens, and no clinical signs or differences in body weight were observed [38]. The mutant identified as S06004ΔSPI2 could not be isolated from the liver more than 2 wk post vaccination or from the spleen more than 3 wk post vaccination; meanwhile, organs from the group infected with the parent strain were positive until 3 wk post infection. Interestingly, chickens orally vaccinated with the mutant SP strain were challenged intramuscularly 10 d post vaccination using the parent strain of SP and SG strain SG9. The survival rate was 100% in the vaccinated group with the mutant strain of SP (S06004ΔSPI2) and 60% in the control group vaccinated with phosphate buffer saline (PBS) and challenged with the parent strain of SP; in the case of vaccination using S06004ΔSPI2 and challenged with SG9, the survival rate was 100% compared to the control group vaccinated with PBS and challenged with the same strain, where this value was 30%. This first study showed the potential of the S06004ΔSPI2 strain as a live attenuated oral vaccine against FT and PD [38]. An additional trial was conducted using this strain, but in this case, the vaccination was performed intramuscularly on 2-day-old white chickens [39], and the challenge occurred 10 d post vaccination by an intramuscular route. The persistence results of vaccine strain S06004ΔSPI2 indicated that this mutant can persist for 14 d, except for one spleen sample that was positive at d 21 post vaccination. Slight clinical signs were observed in groups vaccinated with S06004ΔSPI2 and challenged with SP and SG9, but 3 to 7 days post challenge, the birds did not show any clinical signs. Serum levels of IgG were significantly higher in the vaccinated birds during all observation periods, and cellular immune responses (examined by peripheral mononuclear proliferation assay) were elevated by 14 d post vaccination. Vaccinated birds showed a survival rate of 90% in the group vaccinated with the S06004ΔSPI2 strain and challenged with the SP parent, whereas a survival rate of 10% was observed in the control group; in the case of SG9 challenge, the survival rate was 70% in the vaccinated group using the S06004ΔSPI2 mutant strain, compared with 0% in the control group vaccinated with PBS. The results indicated that S06004ΔSPI2 is a potential live attenuated vaccine to protect chickens against FT and PD. Despite the fact that the results of both studies are encouraging for continued research, LD50 or ID50 must be determined for the SP challenge strain and the S06004ΔSPI2 mutant strain following the recommendation of the OIE [40]. In all aforementioned studies, different SG and new SP vaccine candidates were developed, and a few of them have been used commercially to prevent and control FT in developing countries. The candidates have been tested under laboratory conditions using a few animals, and no replications were performed to demonstrate the consistency of the safety and efficacy results; additionally, the vaccine candidates have not been tested under field conditions. Interestingly, field vaccination programs for preventing and controlling SG used live attenuated and inactivated vaccines together. There is no scientific reason for using both vaccines, and this practice is related to immune concepts of protection based on serological responses, which are probably related to viral vaccines and immune response. Inactivated products fail to elicit a cell-mediated immune response and intestinal colonization [41], responsible for clearing intracellular facultative pathogens, express a limited number of antigens unlike attenuated strains [2], and neither stimulates SIgA responses at mucosal surfaces, the principal mechanism against intestinal colonization [15]. This concept cannot be applied for Salmonella live attenuated oral vaccines because of their mechanisms of action, which activate the mucosal and systemic immune response [2, 15, 42, 43], preventing the adhesion, the first step of Salmonella colonization, and stimulating mucosal and systemic Cell-mediated immune (CMI) responses. Salmonella Vaccines: Homologous or Heterologous Protection and Colonization-Inhibition Effect A holistic approach characterized by the comprehension of the different parts of a Salmonella control program, is the principal tool taking into account all variables involved in which vaccination is a small portion. Salmonella vaccination can be used as part of a comprehensive control and prevention program because a complete immune response is a complimentary tool for controlling Salmonella from infected birds. Live Salmonella vaccines induce better protection than killed vaccines [44], and oral live attenuated vaccines lead to the induction of a strong cellular immune response and mucosal immunity in vaccinated birds. When discussing homologous or heterologous protection, it is necessary to begin by including definitions of the 2 words from a scientific point of view: Homologous is a degree of similarity, as in position or structure, and it may indicate a common origin or a state of similarity in structure and anatomical position, but possibly not in function, between different organisms, suggesting a common ancestry or evolutionary origin. Heterologous means different origins, or the lack of correspondence of apparently similar organic structures as a result of unlike origins of constituent parts. From this point of view, homologous strains belong to the same O9 group of SG or SG biovar pullorum, and inside this group, we can have homologous isogenic strains when all individuals are genetically identical. Regarding homologous and heterologous protection, some work has been done with different approaches. In the 1990s, a study evaluated an experimental vaccination program using a live avirulent Salmonella Typhimurium (ST) strain to protect immunized chickens against challenge with homologous and heterologous Salmonella serovars belonging to different antigenic groups [45]. In this study, the results showed that homologous protection using the vaccine Δcya Δcrp ST was better than heterologous protection and that the protection conferred by the Δcya Δcrp vaccine was significantly different in vaccinated birds compared to unvaccinated chickens. The ST Δcya Δcrp live vaccine reported little effect on the transmission of Salmonella among SE, indicating that heterologous protection does not have good efficacy for protecting birds against Salmonella [46]. Similar results (indicating that cross protection to other antigenically similar serovars was not efficacious) have been published, which confirm that vaccine manufactured with a specific serovar can provide protection against serovars in the same group, but this protection was incomplete because antigenically unrelated Salmonella serovars were not covered by the vaccines [47]. Other studies have demonstrated that SE vaccines can provide homologous protection against Salmonella serovars of the same group, conferring efficacious cross protection against SG infections [35, 36]. Inoculation with attenuated ST vaccines resulted in a weak, but significantly reduced, colonization by ST, and colonization by SE could not be diminished by either of the ST vaccine strains [48]. Homologous protection was described in a trial using a live attenuated SE vaccine against FT in birds and showed good protection under laboratory experimental and field conditions [35, 36]. Recently, a study using a live attenuated ST that primed and boosted immunization by oral route was conducted to evaluate protection against SE, ST, and SG challenge strains, and the results showed that cross protection was significantly efficacious. In this study, SE and ST challenge strains were reduced in the liver, spleen, and cecal tissues in chickens vaccinated with the ST strain, and after SG challenge, mortality was reduced significantly in vaccinated birds. This study suggested that attenuated ST strains can confer protection against ST, SE, and SG infections [49], indicating heterologous protection of an ST strain. In this study, the SG challenge strain caused 55% mortality in unvaccinated birds, compared to 20% mortality in the vaccinated group; curiously, protection against a homologous challenge (ST strain) has higher bacterial recovery than a heterologous challenge with an SE strain 1, 4, and 7 d after challenge. Other studies suggested that dam mutant vaccines reduce Salmonella colonization and contamination caused by a number of heterologous serovars in the poultry industry [50, 51], and these results are similar to those of studies conducted in calves with a dam mutant ST strain that conferred cross protection against virulent Salmonella Newport [52]. In contrast, studies of cross-protective immunity in chickens demonstrated that expression of all interleukins (IL1β, IL17, IL22, and IFNγ), inducible NO synthase (iNOS), and extracellular fatty acid-binding protein (Ex-FABP) was significantly higher against homologous serovars than against heterologous serovars [53]. On the other hand, priming with either ST or SE activates strong cross-reactive protection and considerable protection to challenge with either serovar, suggesting the conservation of protective antigens; SE (O9) or ST (O4) vaccines could provide heterologous protection against serovars belonging to the same or different groups [54]. Evidence in the field in developing countries indicates that this protection may be variable and almost always involves partial or very limited protection against cecal colonization, organ invasion (spleen, liver, ovaries), and fecal excretion. Despite the fact that SG and SP poorly colonize the intestine [55], it was demonstrated that SPI-19 (Salmonella Pathogenicity Island 19) and T6SS (Type VI Secretion System), which are encoded in this region, contribute to colonization of the gastrointestinal tract by SG [56]. The colonization-inhibition effect of the SG vaccines can be exploited based on fecal-oral [47] or respiratory transmission [57] of the bacteria. This recent work suggests a colonization-inhibition concept in which a live Salmonella strain orally administered to day-old chickens can potentially be used as a control method of FT. For the exploitation of this phenomenon in live attenuated SG vaccines for poultry, information on colonization inhibition between wild-type strains of Salmonella enterica subsp. enterica within the same and different serovars is needed [58]. Salmonella strains were shown to inhibit colonization by other Salmonella strains to varying degrees [59]. Moreover, besides stimulating the development of true immunity to the infection, the oral administration of live Salmonella vaccines to day-old chicks also induced a colonization-inhibition effect against other Salmonella strains within a short period of time. Evidence on the specificity of inhibition between Salmonella strains is provided by the facts that a) the best inhibition is produced between isogenic Salmonella strains; b) inhibition between strains of the same serovar is much more effective than between strains of different serovars; and c) the inhibitory effect does not occur between unrelated organisms [60]. The colonization-inhibition effect was tested in vivo [55] between single and mixed strains belonging to the serogroups O4 (former group B), O9 (former group B), O6, O7, and O8 (former group C), and O13 (former group G) in young chickens. The results of the trial showed that the colonization-inhibition effect was the strongest between isogenic strains (strains of the same clone) and that the inhibition effect between SE strains was considerably greater than the effect between ST strains. Almost no inhibitory effect was produced by the rough strain of ST 1464, and none of the ST strains was able to reduce the intestinal growth of the heterologous strain of SE 147NA. SE strain phage type 4 showed very high inhibition against non-isogenic strains, and in some cases, it showed nearly complete inhibition against non-isogenic strains. None of the SE strains was able to influence the cecal colonization of the heterologous strain ST 9098NA. The colonization-inhibition effect is more pronounced between isogenic strains, and there is greater inhibition within a serovar than between serovars [58, 60, 61]. Therefore, protection conferred by oral vaccination with live homologous salmonellae has been shown to induce protection against visceral invasion by the challenge strain with a reduction in the colonization of the gastrointestinal tract [62, 63, 64]. A Regulatory and Practical Overview of FT and PD Vaccines in Developing Countries It is important to remember that there is no inactivated or live attenuated vaccine against SG that is capable of protecting birds against high levels of challenge and that vaccination is a very small part of a control program; however, vaccination is very good tool if production management conditions are efficiently conducted. If there is a safe and efficacious vaccine for controlling FT or PD outbreaks with negligible risk, the challenge of vaccine manufacturers is to perform studies to demonstrate results to enable new vaccination strategies for managing both diseases in developing countries. These studies can support new proposals aimed to reach excellence in controlling host-specific salmonellosis. Currently, the use of SG9R is allowed in some Latin American countries [35], but there are no technical guidelines for testing SG vaccines from a regulatory point of view. The criteria for an ideal Salmonella vaccine have been described extensively, and they include wide protection, attenuation, reduction of intestinal colonization, compatibility with other control measures, cost effective application, and long-lasting protection; in few words, Salmonella strategy should represent a holistic approach for preventing and controlling FT and PD [65]. Interestingly, because of the eradication programs in different regions of the world, live attenuated vaccines to control systemic salmonellosis in poultry do not have any specific guides like monographs in the Pharmacopoeias or other regulations [66, 67]. It would be useful and practical for authorities and manufacturers in developing countries to develop a guideline including all parameters and tests that are necessary for licensing a live attenuated vaccine against FT or PD. Some of the aspects that should be considered are reduced excretion, ability to persist in an environment of vaccinated birds, absence of transmission to eggs, clearance of wild SG from vaccinated birds, safe use during the laying period, no residual virulence, suitable efficacy, and protection of vaccinated birds. A vaccine withdrawal period before slaughter in domestic birds raised for meat or eggs should be required in relevant studies. Standardization guidelines are important because FT and PD vaccines must follow the same rules as those of other Salmonella vaccines. Furthermore, because of FT and PD continue to be a problem in poultry production in Africa, Asia, and Latin America, guidelines are required to guarantee safe and efficacious products. Rules should be similar to those described in 9 CFR 113.100 113.120, 113.122, and 113.123 for inactivated Salmonella vaccines in the United States [66] or as recommended by the European Pharmacopoeia monographs 1947 and 2361 for inactivated SE and ST vaccines or 2520 and 2521 for SE and ST live attenuated vaccines for chickens [67]. From a regulatory point of view, having defined guidelines for vaccines intended for active immunization against SG manufactured from SG strains would help manufacturers and authorities in strain selection and development and in assessing products based on a reference standard, respectively. For example, challenge trials must require DL50, taking into account that in vivo passages can increase the virulence of the SG strain [68]. Some topics for a guideline for SG and SP vaccines are proposed in Table 2. Table 2. Proposed master seed and finished product requirements applicable to vaccines manufactured using SG or SP strains. Topics Information/tests required Selection Strain must have satisfactory safety and efficacy Strain should have a stable marker or suitable identification to differentiate it from wild SG or SP strains DL50 compared to parent/pathogenic strain Development Records of origin, date of isolation, passage, and propagation history Preparation of media, seed cultures, inoculation, incubation, fermentation, titration, and other related materials and methods must be documented Maximum bacterial count regarding safety must be determined Propagation harvest and bulk Identity and purity Morphology and biochemical, serological, and antimicrobial susceptibility All applicable molecular techniques to determine the profile and strain characteristics A suitable method to determine the purity of the master seed must be described Master seed Safety Minimum age of chickens for testing safety, minimum number of chickens, maximum bacterial content applied, observation period Minimum age for vaccination Excretion assessed by reisolation in cloacal and environmental swabs tested weekly in vaccinated and contact chickens Spread assessed by organ culture of liver, spleen, oviduct/ovaries, and cecal content in vaccinated and contact birds Passage in chickens at least 5 times to verify increase of virulence Test must be performed in chickens for breeding/laying of meat production accordingly Immunogenicity Mortality must be reduced in target species/category of birds (P < 0.05) Isolation of challenge strain from organs of vaccinated birds is reduced significantly (P < 0.05) compared to the control group (unvaccinated and challenged) Finished product Identity Bacterial morphology, biochemical, and serological methods, culture, PCR, or other molecular methods Sterility Absence of bacteria and fungi Titration (potency) CFU/dose (bacterial count at release) Storage Stability data at the end of the shelf-life period, for freeze-dried products residual moisture must be included. Storage temperature and shelf life based on stability data must be included. Topics Information/tests required Selection Strain must have satisfactory safety and efficacy Strain should have a stable marker or suitable identification to differentiate it from wild SG or SP strains DL50 compared to parent/pathogenic strain Development Records of origin, date of isolation, passage, and propagation history Preparation of media, seed cultures, inoculation, incubation, fermentation, titration, and other related materials and methods must be documented Maximum bacterial count regarding safety must be determined Propagation harvest and bulk Identity and purity Morphology and biochemical, serological, and antimicrobial susceptibility All applicable molecular techniques to determine the profile and strain characteristics A suitable method to determine the purity of the master seed must be described Master seed Safety Minimum age of chickens for testing safety, minimum number of chickens, maximum bacterial content applied, observation period Minimum age for vaccination Excretion assessed by reisolation in cloacal and environmental swabs tested weekly in vaccinated and contact chickens Spread assessed by organ culture of liver, spleen, oviduct/ovaries, and cecal content in vaccinated and contact birds Passage in chickens at least 5 times to verify increase of virulence Test must be performed in chickens for breeding/laying of meat production accordingly Immunogenicity Mortality must be reduced in target species/category of birds (P < 0.05) Isolation of challenge strain from organs of vaccinated birds is reduced significantly (P < 0.05) compared to the control group (unvaccinated and challenged) Finished product Identity Bacterial morphology, biochemical, and serological methods, culture, PCR, or other molecular methods Sterility Absence of bacteria and fungi Titration (potency) CFU/dose (bacterial count at release) Storage Stability data at the end of the shelf-life period, for freeze-dried products residual moisture must be included. Storage temperature and shelf life based on stability data must be included. View Large Table 2. Proposed master seed and finished product requirements applicable to vaccines manufactured using SG or SP strains. Topics Information/tests required Selection Strain must have satisfactory safety and efficacy Strain should have a stable marker or suitable identification to differentiate it from wild SG or SP strains DL50 compared to parent/pathogenic strain Development Records of origin, date of isolation, passage, and propagation history Preparation of media, seed cultures, inoculation, incubation, fermentation, titration, and other related materials and methods must be documented Maximum bacterial count regarding safety must be determined Propagation harvest and bulk Identity and purity Morphology and biochemical, serological, and antimicrobial susceptibility All applicable molecular techniques to determine the profile and strain characteristics A suitable method to determine the purity of the master seed must be described Master seed Safety Minimum age of chickens for testing safety, minimum number of chickens, maximum bacterial content applied, observation period Minimum age for vaccination Excretion assessed by reisolation in cloacal and environmental swabs tested weekly in vaccinated and contact chickens Spread assessed by organ culture of liver, spleen, oviduct/ovaries, and cecal content in vaccinated and contact birds Passage in chickens at least 5 times to verify increase of virulence Test must be performed in chickens for breeding/laying of meat production accordingly Immunogenicity Mortality must be reduced in target species/category of birds (P < 0.05) Isolation of challenge strain from organs of vaccinated birds is reduced significantly (P < 0.05) compared to the control group (unvaccinated and challenged) Finished product Identity Bacterial morphology, biochemical, and serological methods, culture, PCR, or other molecular methods Sterility Absence of bacteria and fungi Titration (potency) CFU/dose (bacterial count at release) Storage Stability data at the end of the shelf-life period, for freeze-dried products residual moisture must be included. Storage temperature and shelf life based on stability data must be included. Topics Information/tests required Selection Strain must have satisfactory safety and efficacy Strain should have a stable marker or suitable identification to differentiate it from wild SG or SP strains DL50 compared to parent/pathogenic strain Development Records of origin, date of isolation, passage, and propagation history Preparation of media, seed cultures, inoculation, incubation, fermentation, titration, and other related materials and methods must be documented Maximum bacterial count regarding safety must be determined Propagation harvest and bulk Identity and purity Morphology and biochemical, serological, and antimicrobial susceptibility All applicable molecular techniques to determine the profile and strain characteristics A suitable method to determine the purity of the master seed must be described Master seed Safety Minimum age of chickens for testing safety, minimum number of chickens, maximum bacterial content applied, observation period Minimum age for vaccination Excretion assessed by reisolation in cloacal and environmental swabs tested weekly in vaccinated and contact chickens Spread assessed by organ culture of liver, spleen, oviduct/ovaries, and cecal content in vaccinated and contact birds Passage in chickens at least 5 times to verify increase of virulence Test must be performed in chickens for breeding/laying of meat production accordingly Immunogenicity Mortality must be reduced in target species/category of birds (P < 0.05) Isolation of challenge strain from organs of vaccinated birds is reduced significantly (P < 0.05) compared to the control group (unvaccinated and challenged) Finished product Identity Bacterial morphology, biochemical, and serological methods, culture, PCR, or other molecular methods Sterility Absence of bacteria and fungi Titration (potency) CFU/dose (bacterial count at release) Storage Stability data at the end of the shelf-life period, for freeze-dried products residual moisture must be included. Storage temperature and shelf life based on stability data must be included. View Large Unfortunately, most developing countries have developed FT and PD programs by copying successful programs in other regions of the world; however, these programs have not been adjusted based on epidemiological knowledge and updated data on disease situations; also, as mentioned in the sections above, underreporting of outbreaks occurs because of regulatory authority restrictions and the absence of coordination between sanitary official authorities and the poultry industry. As a result, the occurrence of diseases such as FT and PD is unknown, and programs are not based on real information. Consequently, the eradication programs established in most developing countries are impractical because costs have never been assessed. A holistic approach is indispensable to controlling FT and PD in developing countries; the principle of eradication should be reviewed and changed by control programs focused on strategies that consider the coexistence of poultry production and the agents of FT and PD. Based on this analysis, developing countries should apply “therapeutic vaccination,” a concept that means the ability of a vaccine strain to clear the SG or SP bacteria from infected birds, to clear infected cells and prevent colonization and organ invasion after field challenge. This concept could be applied for an ideal SG vaccine, and the poultry industry, vaccine manufacturers, and authorities should work together to control FT and PD in developing countries. FINANCIAL AND COMPETING INTEREST DISCLOSURE L. Revolledo is an independent consultant for the poultry industry in Latin America. The author has no relevant affiliation or financial involvement with any company, organization, or entity with a financial interest in or a financial conflict with the subject matter or materials discussed in this review. CONCLUSIONS AND APPLICATIONS Most developing countries have established eradication or control programs for FT and PD based on theoretical data due to the absence of real information and underreporting of FT and PD outbreaks. Killed vaccines against SG do not elicit a cell-mediated immune response, which is indispensable for clearing the bacteria. Live attenuated vaccines against SG based on the 9R strain have shown good results, but they can be replaced by new products that are the result of newly developed technologies, avoiding the possibility of reversion to a more virulent phenotype demonstrated by gene mutations aceE and rfsj. Live attenuated vaccines based on an SE drift mutant attenuated strain have demonstrated cross protection against FT and have shown clearance of the challenge strain from infected birds; they are an excellent tool for strategies based on “therapeutic vaccination” in developing countries according to the epidemiological situation in the region. Salmonella vaccines have demonstrated protection against Salmonella serovars in the same group, showing that homologous serovars can have efficacious cross protection. Standard guidelines for manufacturing vaccines containing live SG strain are required, and they should be similar to the international rules contained in the European Pharmacopoeia in the European Union or the Code of Federal Regulations in the United States for vaccines manufactured with host-specific Salmonella or non-hot specific Salmonella. New designs and delivery strategies for eliciting mucosal and systemic immune responses are needed in order to develop more efficacious vaccines against FT and PD to prevent and clear infections in poultry, and these solutions should focus on markets in developing countries. Footnotes Primary Audience: Veterinarians, Poultry Researchers, Poultry Industry Personnel REFERENCES 1. Kumar T. , Mahajan N. K. , Rakkha N. K. . 2010 . Epidemiology of fowl typhoid in Hayarna, India . World's Poult. Sci. J. 66 : 503 – 510 . Google Scholar CrossRef Search ADS 2. Desin T. S. , Köster W. , Potter A. A. . 2013 . Salmonella vaccines in poultry, past, present and future . Expert Rev. Vaccines 12 : 87 – 96 . Google Scholar CrossRef Search ADS PubMed 3. Lee Y. J. , Kim K. S. , Kwon Y. K. , Tak R. B. . 2003 . Biochemical characteristics and antimicrobial susceptibility of S. gallinarum isolated in Korea . J. Vet. Sci 4 : 161 – 166 . Google Scholar PubMed 4. 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Journal of Applied Poultry ResearchOxford University Press

Published: Jan 5, 2018

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