What is a correct way to choose a PRRS sow vaccination program? When PRRS vaccination of piglets is needed?

Answered by: Enric Marco

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Piglet vaccination is usually done when we would like to reduce PRRS virus circulation on the growing phase. Vaccine will reduce the amount of PRRS virus shed by viremic animals and also will reduce duration of shedding. Those reductions are not spectacular but can help to control the PRRS virus circulation.
Sow PRRS vaccination is used in two ways. The first one is to bring back to normality the farm after an outbreak; the second one is to help the farm to maintain stability by avoiding PRRS virus recirculation among sows which will produce viremic piglets.
By vaccinating sows, immunity will be higher and more stable helping to reduce subpopulations of sows which we know are the responsible for on farm virus recirculation.

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Eimeria praecox: a brief story of the big unknown of coccidiosis in poultry

Seven species of Eimeria (E. acervulina, E. brunetti, E. maxima, E. mitis, E. necatrix, E. praecox and E. tenella) are recognized to be causative agents of coccidiosis in chickens of the genus Gallus gallus. Until recently, Eimeria praecox was considered to be a non-pathogenic species unable to cause adverse effects in the host. Read more

In fact, in 1970, when Johnson & Reid wrote the milestone article that for the first time standardized and described the scoring scale for lesions caused by all Eimeria spp., Eimeria praecox was not included. It was, and still is, well know that E. praecox is not able to provoke pathognomonic lesions like E. acervulina, E. brunetti, E. maxima, E. necatrix and E. tenella, however even then some researchers were investigating whether this species of Eimeria was truly non-pathogenic.

Peter L. Long in 1968, attempted to demonstrate the adverse effects of Eimeria praecox on the host and for this purpose he compared its effects with those of Eimeria acervulina. His conclusions were that even if E. praecox was less pathogenic than E. acervulina, high doses of oocysts of E. praecox depressed the rate of weight gain and food and water consumption.
Some years later, in 1982, Gore and Long reported that mortality and morbidity are not characteristics associated with Eimeria praecox, however in their studies it was shown to interfere with digestion and consequently cause significantly retarded weight gain. It was the first time that E. praecox was recognized to be economically significant and thus could no longer be considered non-pathogenic.
At the same time, the first prevalence studies were performed and the general outcomes for Eimeria praecox prevalence were quite surprising: this species was shown to be present in many countries all over the globe and with percentages that were far from what was considered to be negligible. See table here. 

From 2003 to 2008 HIPRA also performed several prevalence studies in Europe -namely in Spain, Belgium, Italy and France- and the widespread presence of Eimeria praecox was also confirmed by these (Pagès et al. 2015). 


In 2012 HIPRA performed the first study of Eimeria spp. prevalence in South Africa (Pagès et al. 2015) and there, too, E. praecox was found to be present on 9.5% of farms.
Further confirmation that Eimeria praecox can exhibit a wider range of virulence than previously thought, came in 2009 from a study conducted by Willians et al. where it was observed for the first time that E. praecox was able to cause actual body weight loss and market increases in FCR, as did E. acervulina. Also for the first time, it was observed that the virulence of E. praecox may not only be equal to but may exceed that of E. acervulina.


In the field, single Eimeria species infections are quite rare and most of the time infections involve multiple species. Since Eimeria praecox replicates in the same tract of the gut as E. acervulina -the duodenum- and both impact early in the production cycle, one of the aspects to be investigated was whether during a co-infection with these two species either a competitive exclusion or a synergic effect took place. In 2012, Répérant et al. found that when E. praecox -even with a low infective dose- is inoculated together with E. acervulina, its negative effect on growth was added to the latter and significantly increased compared to a single E. acervulina infection.
Nowadays it is quite clear that Eimeria praecox constitutes one of the major causes of subclinical coccidiosis with repercussions on the productive performances and due to its early impact in the cycle, it is especially important in broiler meat productions where the first weeks are crucial for the overall performance of the birds. It is therefore worth taking into account this species of Eimeria in prophylactic approach to fully protect poultry.
HIPRACOX® was the first attenuated vaccine for coccidiosis in broilers that took this aspect into consideration by also including E. praecox in its composition.

Coccidiosis in poultry: an objective assessment of the incorporation of a rotation programme using precocious attenuated vaccines

Within the scope of assessing new strategies for the control of coccidiosis in poultry, the first factors to consider are always immunological and physiological but also include less objective factors such as the management. However, when these new strategies come to be assessed, the exercise has to be carried out in perspective by evaluating those indicators that are the most critical in order to decide whether maintaining such strategies or to replacing them with others. In the production of broiler chickens, these indicators are solely productive.

Live precocious attenuated vaccines for coccidiosis in poultry like HIPRACOX® have been used in numerous countries and situations, and these experiences serve to support the implementation of vaccine rotation programmes for the control of coccidiosis in poultry.

Over the past 10 years, experiences in the field have provided data regarding this cost/benefit ratio, derived from the use of rotation programmes with precocious attenuated vaccines, such as HIPRACOX®. Having vaccinated several million birds in different circumstances throughout the world, these experiences have enabled us to draw various conclusions.
Minor intestinal injuries
Reduction of the total mean lesion score (TMLS), according to the Johnson and Reid method (1970) for coccidiosis in poultry, in vaccinated and post-vaccination cycles compared to pre-vaccination cycles (Dardi et al. 2015, see image above).
Improvements in production indicators
Production results improved during the vaccination phases and in subsequent cycles where the use of anticoccidial drugs was reincorporated, both in winter vaccine cycles in Spain (Alameda et al. 2015) and in central European farms during the summer (Ronsmans et al. 2015):

Cost-benefit assessment

Production costs per 1,000 kg were reduced, as a result of the birds’ improved performance.


(Alameda et al. 2015) showed that production cost (euros/1,000 kg live weight) was always below average (€923) in the months with vaccination cycles (CDV) compare with previous cycles with anticoccidial drugs (CAV). From the first cycle, there was a positive trend that persisted in all subsequent cycles (CPV). The cost included the value of the vaccine given on the first day of life by coarse spray.

Using precocious attenuated vaccines such as HIPRACOX® against coccidiosis in poultry provides several advantages over traditional programmes based solely on control through the use of anticoccidial drugs. Aimed at broiler chickens in particular, this control strategy is being used in several companies across different countries with optimum results. Ultimately, it has proven a simple tool for reducing the use of antibiotics, as indicated by the major producing countries.

How an adjuvant can modulate the immune response against coccidiosis in poultry

 

EVALON® is a live coccidiosis vaccine against avian coccidiosis in poultry composed of E. acervulina, E. brunetti, E. maxima, E. necatrix and E. tenella. All the strains have been selected to maximize immunogenicity. Avian Eimeria have a complex life cycle with a combination of exogenous and endogenous stages that trigger the immune system of the host. However, Eimeria parasites have also been described as being highly elusive to the immune system as well as producing chemokines than can slow or inhibit the immune response (Jang 2011, Schmid 2014, Miska 2013).

Although it is well known that live vaccines can induce an adequate immunity, we strongly believe that immune modulation is crucial in providing a strong, fast and long-lasting immunity (Dalloul 2005). This could be essential in the prevention of coccidiosis in poultry.

In a study conducted at the University of Zaragoza with Prof. Emilio del Cacho, different groups of birds received EVALON®, EVALON® together with HIPRAMUNE® T and PBS (control group).
HIPRAMUNE® T is a solvent specifically designed to be mixed together with the vaccine EVALON®. It contains a colorant and flavour -to enhance pecking and preening when the vaccine is applied in coarse spray administration- and an adjuvant designed to modulate the immune response. It is the first time that the use of an adjuvant has been considered in a live vaccine intended to prevent coccidiosis in poultry.
Birds from each subgroup were used to obtain intestinal lymphocytes from mucosa and Peyer’s patches at different times post-vaccination.
Results obtained in the first experiment indicated that HIPRAMUNE® T is able to increase the level of Th1 cytokines, as indicated by the results obtained for IL-2. Regarding IFN-gamma, statistically significantly higher levels were detected on different days both in the mucosa and Peyer’s patches. In contrast, levels of IL-4 and IL-10 were equal or lower when the group receiving EVALON® plus HIPRAMUNE® T was compared to the group receiving EVALON® alone. These results confirm the ability of HIPRAMUNE® T to stimulate a cellular immune response. It is therefore hypothesized that EVALON®, when administered together with HIPRAMUNE® T, is able to polarize the immune response towards a Th1 response. This happens with more intensity than the vaccine without the adjuvant. The Th1 response is crucial for protection against Eimeria (del Cacho 2011 and 2012).
In vaccines designed for layers and breeders which are long-lived categories, it is essential to have extended protection throughout the life cycle. Generally, live attenuated vaccines have proved to provide protection until 37 weeks. However, in the case of EVALON®, its efficacy is boosted by co-administration with HIPRAMUNE® T; we therefore wanted to test the duration of immunity until the end of the production cycle of a breeder hen (60 weeks).
In a second study, the duration of immunity was assessed for EVALON® plus HIPRAMUNE® T. The laboratory facilities for the performance of the trials prevented the introduction of external Eimeria oocysts which could provide trickle infections throughout the rearing and laying period. Together with this, birds were not moved from rearing to laying. It is well known that at farm level and after vaccination, trickle infections occur and it is important to maintain and enhance long-term immunity against Eimeria parasites (Williams 2002). In the present study we wanted to prove that protection was extended, even in the absence of trickle infections.
At day 0 a group of one-day-old birds was vaccinated via coarse-spray with one dose of vaccine EVALON® plus HIPRAMUNE® T while another group of birds received only PBS (control). The elimination of oocysts was monitored weekly in litter faeces, as can be seen in the Figure below. After the vaccination peak and once the birds became fully protected, generally no oocysts were detected.


To study the efficacy of the vaccine, birds were randomly selected at different time points (14, 28, 40 and 60 weeks) and individual challenge tests for each Eimeria species included in the vaccine were performed using highly pathogenic heterologous challenge strains. The vaccinated and non-vaccinated birds were compared, the main parameter under consideration being the macroscopic intestinal lesions after the challenge (Johnson & Reid 1970). Other secondary parameters evaluated also included individual body weight, elimination of oocysts post-challenge, clinical signs and mortality.
As an example, data obtained for E. necatrix lesion scoring after challenges is included in the Figure below. Similar results in terms of a significant reduction in lesions in vaccinated groups were obtained for all the other Eimeria species included in the vaccine.


The results obtained indicated an extended duration of immunity with EVALON® when administered together with the adjuvanted solvent HIPRAMUNE® T in conditions that do not favour the presence of oocysts in the litter. The duration of immunity was confirmed at 60 weeks post vaccination.

Immunology in coccidiosis in chickens: The role of cytokines IL-2 and IFN-gamma

The cellular and molecular mechanisms leading to immune protection against coccidiosis in chickens are complex and include multiple aspects of innate and adaptive immunity. Innate immunity is mediated by subpopulations of immune cells that recognize pathogen-associated molecular patterns. Adaptive immunity, which is important in conferring protection against secondary infections, involves subtypes of T and B lymphocytes that mediate antigen specific immune response. Experimental studies in coccidiosis in chickens now support the role of lymphocytes and their secreted products (Lillehoj et al. 2011)

Eimeria parasites have a long and complex biological cycle with exogenous and endogenous phases that trigger the immune system of the host. These parasites that cause coccidiosis in chickens can produce substances (chemokines) than can inhibit the immune response.

It is well-known that coccidiosis vaccines can generate a proper level of immunity but at HIPRA we worked on the hypothesis that if we were able to modulate the immune response in some way we would be able to generate a strong, fast and long lasting immunity (Dalloul et al. 2005).

In coccidiosis in chickens there are 2 types of immune response addressed by two types of cellular populations: those producing interleukins Th1 (IL-2 and IFN-gamma) and others that produce interleukins Th2 (IL-4 and IL-10). To enhance the control of the parasite through cytotoxicity mediated by antibodies it is very convenient to shift the immune response towards Th1without eliminating the synthesis of interleukins type Th2.
A Th1 immune response will improve the production of specific cells such as macrophages and Natural Killer cells (NK). Interleukins IL-2 and INF-gamma play an important role in this immune response. IL-2 is responsible for the evolution of the primary T-cells towards a Th1 response and IFN-gamma will allow a differentiation of the non-differentiated cells into macrophages and NK-Cells.
When a pathogen enters the bird, it is initially contained by physical barriers but if it is able to penetrate and successfully infect it, the innate immunity is going to take an active role. At this point in a primary infection, macrophages are very important. They will capture the pathogen, digest the proteins and present them. Together with macrophages, dendritic cells and B cells are specialized antigen presenting cells that will activate naïve T-cells. Antigen Presenting Cells in fact are seen as the link between innate and adaptive immunity. Once the adaptive immunity is created, this will provide a specific response that will eliminate the pathogen.
In the case of an intracellular pathogen, which is the case with Eimeria in coccidiosis in chickens, there will be an activation of IL-2 that will switch the response to a Th1 response. In the Th1 immune response, activated Cytotoxic T-cells (CTL) are able to detect infected cells and destroy them.
CTL will target schizonts and sexual stages of the parasite. This will produce IFN-gamma and activation of macrophages and NK cells. When this Th1 response is successful, the intestinal damage caused by the parasite stops and there is a dramatic decrease in the elimination of oocysts.
If, on the other hand, we have an extracellular pathogen, it is more convenient and effective to have antibodies against this pathogen. IL-4 will lead to a Th2 response. This is what the parasite wants because it is less effective; in fact, the Eimeria parasites have coded in their genome the right proteins to immune modulate the host to have this type of response. The B-cell response will increase IL-10 that will activate eosinophils, mast cells and basophils that are all important in an inflammatory process.
In the studies conducted by HIPRA we wanted to follow the production of Th1 cytokines (IL-2 and IFN-gamma) and Th2 cytokines (IL-4 and IL-10). In this way we could better understand all the mechanisms involved in this process and look for adjuvants that were able to modulate the immune response against coccidiosis in chickens.

What we have learned about PRRS disease after 20 years?

The Porcine Reproductive and Respiratory Syndrome has been the disease that has changed many ideas in global pig production in the same way as HIV did in the human population. Listening to the testimonies of opinion leaders in this video, it is fair to say that we have learned a lot and that the video captures two visions: that of the scientists and that of the practitioners.

Conceptually, there are certain similarities between the PRRS and AIDS, the latter appearing in the 1980s, whilst PRRS appeared in the 1990s. In both cases, they are very serious diseases in the affected populations and despite the fact that there is still no cure, there has been much progress in our knowledge of the viruses that are responsible for them, and how to improve control strategies for them. Improved biosecurity in pig production is equivalent to the educational measures used to reduce the risk of sexual transmission. 
Fortunately, today the mortality associated with HIV, despite having been very high, has been dramatically reduced and is associated with concomitant diseases, sounds familiar? 
There are also major differences between the two syndromes – the acquired immunodeficiency syndrome remains a potential cause of death throughout the world, with an estimated 37 million affected individuals* and, making a rapid calculation on the basis of a population of some 7,000 million, this means about 0.5% of the world population, and this is where it differs radically from the PRRS virus, as only 5% of the world pig population is considered to be free of the Porcine Reproductive and Respiratory Syndrome. 
If we look back to the first cases of both diseases, a great deal of time and money has been invested in deepening our understanding of both syndromes and in both cases there has been a great deal of progress so that today it is possible to live with both viruses and lead a dignified life as an AIDS sufferer or achieve an acceptable level of production if you are a PRRS-positive producer. 
Indeed, it is one of the lessons that our opinion leaders (the practitioners) have learned, we have learned to live with the disease, although there is still a great deal to learn because, as Alberto Stephano says, just when you think you know everything there is to know about the PRRS virus, you get PRRS again. The approach by our colleague Carlo Lasagna using an (Italian style) football metaphor is also worthy of note, firstly defence (biosecurity) and then good attacking (optimization of control measures). 
As for the scientists, we have learned how to diagnose it, monitor it, sequence it and even how it interacts with the immune system or how it evades it, we have learned how it can mutate or vary genetically, and a key area in which there has been a great deal of research (especially by American universities) has been the main routes of transmission of the disease (as with HIV, the greatest efforts have been devoted to minimizing transmission). 
Key aspects on which work is being carried out in the sector are biosecurity, both external and internal, and immunization etc., which should be understood as a series of measures, because if they are taken separately, the probability of failure increases exponentially. 
Following a more modern approach, Darwin Reicks points to air filtration for the control of aerosols and also, more recently, the probability of working with animals that are genetically resistant to the Porcine Reproductive and Respiratory Syndrome virus.