by Boehringer Ingelheim Animal Health USA Inc./November 12, 2020
Introduction
The goal of every swine veterinarian is to solve health challenges with effective tools to promote well-being and production performance. Porcine proliferative enteropathy (PPE), or “ileitis,” is one such health challenge. Thankfully, the swine industry has had an effective tool to help in controlling this disease for 20 years.
PPE was first described by Biester and Schwarte in the 1930s, who reported on field cases and experimental reproduction of disease (Biester and Schwarte, 1930). They described epithelial proliferative lesions in the intestines of swine that were reproducible by feeding intestinal contents and mucosal scrapings to susceptible pigs. The etiology could not be determined at the time, and they commented that animals in field cases were infected with Salmonella, which they thought could potentially contribute to the disease. In the 1970s, the research group of Dr. Gordon Lawson began investigating this disease, and made crucial findings (Gebhart and Guedes 2010). Gebhart, et al. (1993) found that the bacterium responsible for proliferative enteropathy was a new species that was named in 1995, Lawsonia intracellularis. This was after much effort to achieve pure cultures of the bacterium and to fulfill Koch’s postulates (Lawson and Gebhart 2000; McOrist, et al. 1995; Gebhart, et al. 1993). Six years later, in 2001, the first vaccine against the disease, ENTERISOL ILEITIS, was launched in the United States.
ENTERISOL ILEITIS use in controlling PPE
ENTERISOL ILEITIS is an oral live attenuated vaccine, containing a nonvirulent strain of L. intracellularis to mimic natural infection and induce mucosal immunity with one dose. The efficacy of ENTERISOL ILEITIS against PPE was first demonstrated by Kroll, et al. at the 31st AASV Annual Meeting in 2001. The study showed that providing vaccine in the drinking water to pigs conferred immunity and significantly reduced the colonization of L. intracellularis as well as gross and microscopic lesions (Kroll, et al., 2001). These findings were reproduced and peer-reviewed in 2004, when Kroll, et al. (2004a) proved the vaccine could be provided both by oral drench and in the drinking water of pigs to confer significant protection against PPE.
Field studies followed; at the 33rd AASV Annual Meeting, J. Kolb and F. Sick (2003) presented a summary of five field trials evaluating the efficacy of ENTERISOL ILEITIS in the United States. This evaluation included a total of 55 grow/finish groups, with over 46,900 vaccinated pigs. Kolb found that average daily gain (ADG) was significantly improved in all five trials (P < 0.05), and mortality and cull rates were also improved in the herds that were experiencing clinical signs due to PPE. McOrist & Smits (2007) conducted a randomized, blinded, negative-controlled clinical field efficacy study to evaluate the effect of ENTERISOL ILEITIS in three herds in Australia. The authors found that vaccination improved ADG, and concluded it was efficacious in conditions of both clinical and subclinical presentations of PPE. Since then, several studies have evaluated ENTERISOL ILEITIS under different field conditions and in different countries, including Mexico, Germany, the Philippines, Japan, the Netherlands, Finland, Denmark and South Korea. All of these studies demonstrated improved performance metrics with the use of ENTERISOL ILEITIS (Diaz and Chevez, 2006; Viekilde, et al., 2006; Bulay, et al., 2006; Yamaguchi, et al., 2006; Voets and Hardge, 2006; Klien, et al., 2010; Park, et al., 2013; Schuttert and Seenaert, 2014; Peiponen, et al., 2018; Ochoa, et al., 2020).
It is important to consider as well that ENTERISOL ILEITIS has not only been shown to be an important tool in grow/finish herds but also in protecting gilts and sows against PPE and the hemorrhagic form of PPE, porcine hemorrhagic enteropathy (PHE). Soon after the launch of the vaccine, Waddell, et al. (2003) described a vaccination protocol in a newly constructed 1,250-sow breeding farm (gilt multiplier) and its downstream gilt offspring wean/finish site, in which immunization against L. intracellularis rather than routine feed or water antibiotic medication was used to prevent and control PPE. They observed no outbreaks of any form of PPE at either site in spite of the complete absence of any feed or water antibiotic use when immunizing animals. They also noted that non-vaccinated gilts from this same original gilt source that were shipped to at least three different non-vaccinated herds during this same stocking time frame did experience PHE outbreaks. Candor, et al. (2008) found similar results, in which administering one dose of ENTERISOL ILEITIS to gilts prior to their selection and shipment led to the cessation of deaths, and clinical signs from PHE. Sanford (2006) performed an evaluation of clinical cases of PPE in gilts after vaccination and found field observations that would suggest the duration of immunity for ENTERISOL ILEITIS–vaccinated gilts is at least 2 years, and probably greater than 31/2 years. A reduction in cases of PHE has also been observed in grow/finish pigs when implementing vaccination in piglets (Seo, et al., 2016).
These studies and results demonstrate that one dose of ENTERISOL ILEITIS, given by oral drench prior to weaning or through the water in later ages, is effective in promoting improved production performance and controlling disease under various field conditions. Maternal-immunity interference has not been found to be an issue with this vaccine when used properly (Kroll, et al., 2004b).
Vaccination as a tool to reduce antimicrobial use
Several of the studies that implemented ENTERISOL ILEITIS vaccination noted a beneficial reduction in the use of antimicrobials on the farm. Voets and Hardge (2007) evaluated this specific effect on three different systems. They found it was possible to remove a substantial amount of antimicrobials with the use of vaccination and maintain, if not in some cases improve, performance. Nerem (2009) investigated performance differences between continuous tylosin in feed during finishing versus a protocol of receiving one dose of ENTERISOL ILEITIS prior to entering the finisher. This study also concluded that it is possible to change from routine use of antimicrobials in the finisher to prevention of PPE by vaccination without sacrificing performance. It was also noted that vaccination was the most economical strategy.
As it pertains to feed additives, it is interesting to consider that some feed additives have been found to promote or act in synergy with ENTERISOL ILEITIS. Bourgot, et al. (2017) investigated feeding sows a short-chain fructo-oligosaccharide (scFOS) prebiotic during the last third of gestation and throughout lactation. They found that maternal supplementation of scFOS led to an increase of L. intracellularis–specific immunoglobulin A (IgA) levels in piglets that received ENTERISOL ILEITIS. Muller, et. al. (2018) investigated the supplementation of pigs with a zinc amino acid complex while receiving ENTERISOL ILEITIS and subsequent L. intracellularis challenge. They found that in comparison to vaccination alone, the combined use of ENTERISOL ILEITIS and zinc amino acid complex led to a greater reduction in mortality than vaccination alone. The effects of zinc on the immune system have been known for some time, and have also been found to help the pig respond to an L. intracellularis challenge (Leite, et al., 2018).
While a medication-free window of three days prior to, and three days following, vaccination are needed when implementing ENTERISOL ILEITIS vaccination, not all antimicrobials affect the vaccine. Husa, et al. (2010) showed that administration of ceftiofur or tulathromycin did not alter vaccine efficacy. High levels of zinc oxide as well as acidic conditions have also been previously found to not affect ENTERISOL ILEITIS (McOrist and Smits, 2007).
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The cost of PPE and return on investment of vaccination
Reduction in the use of antimicrobials is also a factor that contributes to the return on investment of ENTERISOL ILEITIS. Voets and Hardge (2007) reported a 53% reduction of antibiotic usage and an $8.60 higher economic benefit per pig in one system that began the use of ENTERISOL ILEITIS. The cost of PPE has recently been updated by Dr. Holtkamp to range from $5.98 to $17.34 per marketed pig (Holtkamp, 2019). According to Holtkamp, the major source of economic losses associated with ileitis arises from productivity losses caused by the disease. The disease may also result in an increase in the percentage of culled pigs, and in some cases, it may cause mortality. J. Kolb and F. Sick (2003) found a benefit, cost ratio greater than 7:1 in a summary of five field trials, as compared to maintaining a conventional continuous feed-medication program for ileitis. More recent trials have found increased revenue of $4.80, $4.10 and $5.93 per marketed pig based on production performance with the implementation of ENTERISOL ILEITIS vaccination (Ochoa, et al., 2020; Peiponen, et al., 2018; Park, et al., 2013).
Immunity to L. intracellularis infection and vaccination
Recently, it has been shown that L. intracellularis can replicate inside of macrophages (Pereira, et al., 2020). Macrophages are a significant antigen-presenting cell, and can be recruited to many sites of the body, including the intestine (Tizard, 2020). It has also been recently shown that when given time to replicate, within three days, L. intracellularis is capable of inducing the expression of inflammatory cytokines such as TNF and IL-8 by activation of the innate immune system (Leite, et al., 2019). This combination of replication, not only in enterocytes but also in macrophages, and the ability to induce inflammatory cytokines, is likely significant for the induction of a robust immune response. This is especially true for the induction of a cellular mediated immune response and activation of CD8 cytotoxic T cells. The latter recognize intracellular antigens and have been suggested to be the main drivers of protection against PPE (Cordes, et al., 2012; Tizard, 2020).
Studies have also measured the humoral immune response to L. intracellularis and vaccination. While ENTERISOL ILEITIS does not generally lead to seroconversion in animals, a commercial killed bacterin vaccine does (Kroll, et al., 2004a; Roerink, et al., 2018). Serum antibody levels are not correlated with protection from PPE (Kroll, et al., 2004a; Roerink, et al., 2018). Interestingly, it has been found that oral vaccination with ENTERISOL ILEITIS not only leads to the generation of L. intracellularis–specific IgA in the ileum of animals, but also, L. intracellularis–specific IgG can be found in intestinal mucosal tissue. Another interesting observation is that not only oral administration, but also intramuscular administration of ENTERISOL ILEITIS, can lead to L. intracellularis–specific IgG levels in the gut (Nogueira, et al., 2015).
The Future
As the field of veterinary medicine progresses, so does our understanding of what leads to health, disease and production performance. The gut microbiome, the community of all microorganisms found in the intestine, has been a recent research focus, since a strong association has been found among gut microbiome composition and overall health and production performance (Kim and Isaacson, 2012; Neiderwerder, 2017). We have found that L. intracellularis not only can lead to lesions, diarrhea and decreased performance, but also to a significant change of the gut microbiome community (Bocherwitz, et al., 2015; Leite, et al., 2020a). Interestingly, we have also found that ENTERISOL ILEITIS, in addition to the aforementioned effects in reducing lesions, clinical signs, improving performance and inducing an immune response, also leads to changes in the composition of the gut microbiome. One of the immediate consequences discovered about this effect in gut microbiome composition was reduced Salmonella shedding in co-infected animals (Leite, et al., 2018; Visscher, et al., 2018). This is significant, as it could have consequences for the transmission of Salmonella as well as the promotion of food safety. A change in microbiome composition induced by ENTERISOL ILEITIS has also been associated with a significant reduction in L. intracellularis shedding in vaccinated animals (Leite, et al., 2020b). These results suggest that ENTERISOL ILEITIS prevents not only lesions and traditional measures of disease, but also prevents negative impacts that L. intracellularis infection can have on the gut microbiome, which are likely to cause increased susceptibility to other pathogens and decreased intestinal function. The other impacts this could have, as we better understand the relationship of gut health and the gut microbiome on overall health, remain to be seen.
While the aforementioned studies have set the standard for vaccination protocols for PPE, there is still room for more investigation and questions to be answered. Interestingly, successful but temporary eradication of PPE has been achieved when focusing on achieving a negative sow and gilt population (Pia, 2000). Recently, Patton, et al. (2021) have described that peri-parturient sows do shed L. intracellularis, and, in fact, the pathogen can be detected in the farrowing crate environment. This raises many questions as to the significance of dams as a source of L. intracellularis infection in later stages of production, and consequently, if there is any value in changing current vaccination protocols. It must also be considered that one of the hypotheses for the occurrence of PHE, versus the chronic and non-hemorrhagic form of PPE, is exposure of older naïve animals to L. intracellularis. Thus, eradication attempts may also benefit from the immunization of animals to prevent this costly form of the disease (Collins, 2013).
As it pertains to vaccination protocols, recent research has also found that ENTERISOL ILEITIS can confer immunity when administered intramuscularly along with 3FLEX® vaccine (Beckler, 2020). Although this vaccine combination and route of administration remain off label, and cannot be recommended, it may also provide direction for future development efforts.
Conclusion
Few swine vaccines have had the long track record, efficacy and supporting data that ENTERISOL ILEITIS has. The future is bright as we better understand all of the benefits of ENTERISOL ILEITIS and refine ways to use this significant tool to promote swine health and production.
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