porcine reproductive and respiratory syndrome

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4 th International Symposium on Emerging and Re-emerging Pig Diseases – Rome June 29 th – July 2 nd , 2003 routes. They can be susceptible to as few as 100 CCID50 of wild-type PRRSV given intramuscularly (7). Viremia - Wild-type PRRSV infection will usually produce a viremia (detected by virus isolation) for a duration of less than 3 weeks with a majority of old swine having a viremia lasting less than 2 weeks. Transmission - Horizontal PRRSV transmission from old swine to age-matched animals after 6 weeks of infection is unlikely under experimental conditions (5,33,34). However, there is one experimental report of PRRSV being transmitted 99 days-post-infection from sows to finishing age swine (67). Interestingly, under field conditions PRRSV may or may not easily transmit among sows within a naïve herd (even when they share a common water trough). Why there are these apparent differences in transmission rates between naïve herds is unknown. Field evidence suggests chronic PRRSV shedding occurs at a low frequency in old swine. This statement is based on collective field evidence where a sow herd regains normal production following a PRRS epidemic and eventually many of the sows become seronegative and sentinels introduced into the sow herd do not become infected. The occurrence of PRRS-positive farms becoming PRRS-negative (22) suggests there are few sows in the herd that are chronically shedding PRRSV. These PRRS-positive herds that are clinically normal and eventually produce PRRS-negative pigs are referred to as PRRS-stable farms. As is the case all too frequently with PRRS, there are few, if any, absolute PRRS rules. Surely, there are times when sows do become infected with PRRSV and shed virus for extended periods of time. Perhaps these chronic shedders are what help keep some herds PRRS-unstable. To reinforce the comment "there are few, if any, absolute PRRS rules, one should keep in mind that subclinical PRRSV infections can occur in a herd. Vertical transmission is more likely to occur later in gestation than earlier and transplacental infection can occur within a week post-infection of the sow (14,29,30,35,36). PRRSV infection of the dam around the time of conception may have little direct impact on embryos, however, once they begin implantation, they may be more susceptible to PRRSV infection (49,50). Boars - Boars can shed PRRSV in semen for many weeks post-infection and in one case out to 92 days post-infection (15). Virus can be shed in semen intermittently, making negative semen tests from PRRSV-seropositive boars difficult to interpret. The quantity of virus shed in semen is not clear. This is an important issue if the amount of virus shed in semen is below the sensitivity of the test used to detect PRRSV in semen, yet this amount of virus is still infectious. The minimal infectious dose of PRRSV in semen for a sow is not known. Young Swine Susceptibility - Young swine also can be infected by the routes described above and pigs can be susceptible to as few as 20 CCID50 PRRSV given oronasally (66). Viremia - Wild-type PRRSV infection will usually produce a viremia (based on virus isolation) for a duration less than 7 weeks, a majority will have a viremia lasting less than 5 weeks. Transmission - Pigs infected with PRRSV have consistently shed virus up to 6 to 8 weeks-post-infection to age-matched pigs (57,62,65). One study reported virus transmission at about 22 weeks-post-infection to age-matched controls (1). 30 Congenitally infected pigs have shed virus to age-matched controls up to about 15 weeks-post-parturition (8). Persistence - In experimentally-infected pigs, PRRSV could be detected by virus isolation for 105 (27) and 150 days (2) post-infection and by PCR for up to 251 days post infection (63). Under field conditions it is assumed that PRRSV could persist in some pigs for even longer periods of time and these pigs could be a transmission risk. However, the significance of these animals as a transmission risk is unknown. In congenitally-infected pigs PRRSV nucleic acid was detected in the buffy coat for up to 230 days after parturition (8). In all of these studies that have detected virus or viral nucleic acid for extended periods of time post infection, the animals were always reported to be seropositive based on the methodology used in the respective laboratories. Immunotolerant - A PRRSV immunotolerant state may not exist in swine. Immunotolerance can be defined as a fetus that becomes infected with a pathogen early in gestation before the fetal immune system develops. The infection does not kill the fetus and as the fetal immune system develops the pathogen is recognized as normal fetal tissue. The fetus is born alive, is replicating the pathogen, sheds the pathogen for life, and has no detectable humoral immune response against the pathogen. Perhaps the best example of an immunotolerant state is the infection of the bovine fetus with bovine virus diarrhea virus (BVDV). The BVDV immunotolerant calf is a critical factor in the epidemiology of the disease since it is difficult to detect them and they shed virus to their penmates. In regards to PRRSV, a hypothetical immunotolerant pig could have tremendous impact in today's production systems where one pig could come into contact with thousands of pigs. I have only tested fetuses as young as about 40 days of age with wild-type or attenuated PRRSV infections and have not been able to prove that PRRSV can induce an immunotolerant state in pigs (32). Wild-type PRRSV eventually kills the fetuses, so little or no chance for the development of an immunotolerant state. Fetuses can be infected with attenuated PRRSV and they appear normal; however, they do develop a detectable immune response and the PRRSV-infected fetuses therefore are not immunotolerant. I think it would be a remote possibility that pigs could develop an immunotolerant state, i.e., a congenitally PRRSV-infected pig that does not develop a detectable humoral response to PRRSV and readily sheds PRRSV. Keep in mind that fetuses infected late in gestation can be born alive and may not have seroconverted by the time of parturition. However, if the pigs survive long enough, they do seroconvert. Indirect Transmission - Indirect transmission defined as PRRSV transmitted between swine that does not involve direct transmission. Possible modes of indirect transmission include aerosol, fomites, and vectors. Aerosol transmission is defined as the transfer of virus from one pig to another via movement of the virus in air. Field observations support this concept, perhaps over a considerable distance (28). Experimental observations support this concept over a distance of about 1 meter (11,58). Fomites are objects that can be contaminated with a pathogen at one place and when moved to another site the pathogen is transferred, e.g., PRRSV-contaminated boots, gloves, needles, and semen-storage coolers (18,19,44). A vector would be a carrier of a pathogen from one pig or farm to another pig or farm. Mechanical vectors could be a PRRSV-contaminated creature, e.g., birds (carrying contaminated manure or feed on feet), blood-
4 th International Symposium on Emerging and Re-emerging Pig Diseases – Rome June 29 th – July 2 nd , 2003 sucking insects (transfer of virus contaminated blood) (45,46), animal (transfer of contaminated material on feet or fur) or people with dirty hands (44). Biological vectors are a creature that can actually replicate the pathogen and amplify the quantity of pathogen; in the case of PRRSV some waterfowl may be a biological vector (63). Current studies at the University of Minnesota are evaluating if mosquitoes can be a biologic vector for PRRSV. Mice and rats have not been susceptible to a PRRSV infection (26). Based on field observations and experimental studies, it seems that all of the previously described routes of indirect transmission are possible. The debate is about the probability of indirect PRRSV transmission by one of these routes and how to prevent that route of virus transmission. IMMUNOLOGY Although there is a growing body of research about PRRSV immunology, this area is still full of unknowns. At the pig level there are some consistent facts about the PRRSV-specific immune response that can be experimentally reproduced. However, these immune responses are not yet fully understood at the cellular and molecular levels. Of course, there are some presumed PRRSV-specific immune responses that are not understood completely at any level, specifically the debate over PRRSV-induced immunoregulation. Depending on methodology and the parameters tested, PRRSV may have inhibitory and/or stimulatory effects on the immune system that may or may not contribute to a synergism between PRRSV and other pathogens. Again, this subject is beyond the scope of this paper and for the sake of brevity, the PRRSV immune response will be thought of in a simplistic fashion. The focus of this section is on how the immune response can relate to control and prevention of PRRS. It is clear that swine experimentally infected with wild-type PRRSV develop a detectable humoral immune response within 7 to 10 days of infection (2,27,30,35,63). Peak antibody titers may occur by 5 to 6 weeks post infection and then the titer may slowly decline over the course of months to where the antibody levels are at the threshold of detection. A virus neutralizing antibody response develops about 4 weeks post infection and may be detectable for months. An interesting field observation that has been repeated in animal studies is the apparent lack of a classical anamnestic humoral immune response to a homologous PRRSV challenge, i.e., when the pig is exposed twice to the same virus there is no detectable rise in antibody titer after the second exposure (29-31). In addition, there is no clinical disease associated with the homologous challenge and no detectable replication of the homologous challenge virus except for one report where virus was only detected 3 days post challenge (53). When it comes to heterologous virus exposure, i.e., the second PRRSV exposure (challenge virus) is a different strain than the first PRRSV exposure (immunizing virus), a rise in antibody titer following challenge is usually detected (10,31,33,37-39,59). It seems reasonable that the postchallenge rise in antibody titer is in response to a set of different PRRSV antigens and this response is not a classical anamnestic immune response. Furthermore, it seems probable that the more antigenically related the PRRSV strains, the less likelihood that a heterologous challenge would induce a detectable humoral response. A lack of cross-protection following heterologous challenge can be characterized by an onset of clinical disease and/or the detection of challenge virus replicating in immunized swine. Cross-protection can be defined as no clinical disease, a 31 failure to detect replicating challenge virus, and no detectable rise in antibody titer. In regards to PRRSV, there is great genetic diversity, and presumably, antigenic diversity among PRRSV isolates. When it comes to control and prevention strategies, this diversity leads to many cross-protection questions that need to be answered. Serologic tests are a very important tool for use in control and prevention programs. In the United States a commercially available ELISA has performed well (PRRS HerdCheck, IDEXX Laboratories, Westbrook, Maine, USA) (52). According to the manufacturer, an ELISA S/P value equal to or greater than 0.4 is considered a positive result for the presence of PRRSV antibody and the assay has a sensitivity of 97.4% and specificity of 99.6%. Under experimental conditions the test is essentially 100% specific and 100% sensitive when testing serum from acutely infected swine. Chronically-infected swine have declining PRRSV antibody titers that are reflected with a decreasing S/P ratio that may fall below 0.4 within a few months of infection. In these situations (S/P < 0.4) it is easy to consider the serum sample positive since the history of the animal is known. In general, the range of the S/P ratios for the "false-negatives" is about 0.2 to 0.4. False-positives with this assay under field conditions may run up to 2 to 3% and most of the S/P values are around 0.4 although higher values have been observed on occasion. In our laboratory about 98% of the negative animals tested (mostly pigs) have had a S/P value less than 0.1 (mostly 0.00) and the remaining negative animals had S/P values ranging from 0.1 to less than 0.4. VACCINOLOGY Perhaps the best way to start this section is to answer the question, Why vaccinate? Well, one would vaccinate against a pathogen to prevent or attenuate the losses associated with a future infection of that pathogen. This is a simple concept until the pathogen is PRRSV, then the use of PRRSV vaccine becomes a complex issue. In the case of PRRS, one could hypothesize that it would be difficult to develop a traditional vaccine for this disease that would be efficacious. The reason for this statement is that under natural conditions, PRRSV-infected swine do not rapidly develop a protective immune response that clears the virus from their body, at least when compared to other swine viruses like swine influenza virus or porcine parvovirus. It appears that it may take several months for a normal pig's immune system to clear a wild-type PRRSV infection from its body. One could surmise that a vaccine would not stimulate any stronger of an immune response than wild-type virus. In fact, the vaccineinduced immune response might even be "weaker" than a wild-type virus immune response. Current commercially available PRRSV vaccines are produced as modified-live virus vaccine (MLV) or as inactivated or killed whole-virus vaccine (KV). In some countries (at least in the United States) autogenous KV may be commercially available. These are vaccines prepared specifically for a single herd from PRRSV isolated from that herd. Attenuated vaccine or MLV Susceptibility - Under experimental conditions, essentially all young and old swine will become infected with MLV when they are given a full dose according to vaccine label (23- 25,37,43,54). Anecdotal field reports indicate that not all MLV-vaccinated swine will seroconvert. The incidence of this failure to seroconvert following vaccination is not clear, nor is it clear as to what might contribute to a failure of seroconversion. Understandably, improper handling or administration of vaccine virus could contribute to a failure of seroconversion, what other factors may play a role is unknown. As previously described, there is the lack of a
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