Control Tools

• Diagnostics availability

• Commercial diagnostic kits available worldwide

  World wide availability of diagnostic kits (PCRs, ELISAs).

  List of commercially available diagnostic kits (Diagnostics for animals).

  GAPS:

  • Due to extreme genetic variability of PRRSV there is no guarantee of detection of all circulating isolates by PCR. Constant validation and updating of applied PCR assays is necessary.
  • Differential ELISA tests discriminating between PRRSV-1 and PRRSV-2 would be handy.

• Commercial diagnostic kits available in Europe

  Freely available

  GAP:

  Do they detect all circulating isolates?

• Diagnostic kits validated by International, European or National Standards

  Yes

  GAP:

  Do they detect all circulating isolates?

• Diagnostic method(s) described by International, European or National standards

  The standards for PRRS diagnostic are summarized by the OIE in the Manual of Diagnostic Tests and Vaccines for Terrestrial Animals (Chapter 3.8.6).

• Commercial potential for diagnostic kits in Europe

  High potential

  GAP:

  Do they detect all circulating isolates?

• DIVA tests required and/or available

  Not available, very desirable.

  GAP:

  In the future it is essential to develop marker vaccines together with accompanying ELISAs that could differentiate vaccinated animals from infected ones.

• Opportunities for new developments

  GAP:

  We need a European system for continuous monitoring of outbreaks. The virus should be isolated and sequenced so that genetic changes can be monitored, diagnostic kits and vaccines updated if necessary.

• Vaccines availability

• Commercial vaccines availability (globally)

  Inactivated and attenuated vaccines are available with both PRRSV-1 and PRRSV-2 strains.

  GAPS:

  • It should be demonstrated that the vaccines work against strains that are isolated during PRRS outbreaks in vaccinated herds. What about the protection against new emerging strains?
  • Would be interesting to have a predicting diagnostic system that could indicate the degree of protection of a vaccine against a specific strain.
  • Mechanisms and criteria of cross protection.
  • The influence of attenuated vaccines on the virus evolution.

• Commercial vaccines authorised in Europe

  Inactivated (PRRSV-1) and attenuated vaccines (both PRRSV-1 and 2) are available.

• Marker vaccines available worldwide

  None

• Marker vaccines authorised in Europe

  None

• Effectiveness of vaccines / Main shortcomings of current vaccines

  Inactivated vaccines area safe but not efficacious, as it has been demonstrated that they cannot control viremia post-challenge by themselves. They can only boost the existing immune response in sows. Inactivated vaccines do not protect naïve animals and give only boost reactions when the animals have been previously exposed to field virus or MLV vaccines.Modified Live Vaccines (MLV) have been proved to be able to reduce clinical signs, viremia and shedding post-challenge, as well as reduce virus transmission in vaccinated populations. With regards to safety, some limited horizontal and vertical spread can be found, as well as vaccine strain shedding. These characteristics differ between vaccine strains. Although initially it was thought that efficacy of attenuated vaccines depends on the level of homology to the field virus, it has been proved lately that this is not the only nor the most important factor. Vaccines efficacy also depends on the capacity of the vaccine to induce cellular immunity and, probably, virus-neutralizing antibodies. Nevertheless, vaccine efficacy is always partial. Therefore, there is an urgent need for new generation vaccines that could provide universal protection. Additionally, it would be highly appreciated to differentiate vaccinated animals from infected ones, so DIVA vaccines would also be desirable. To achieve this development, new approaches of vaccine production should be considered, such as multivalent vaccines or subunit vaccines. Commercial companies in the field are interested but there are no vaccines available that induce universal protection. Therefore, there is an urgent need for a new generation vaccines.

  GAPS:

  • New generation vaccines that induce universal and total protection.
  • Multiple reports (mainly from China, where several vaccines were recently marketed to control HP-PRRSV infections) describe reversion to virulence and/or recombinations of vaccine and field strains. Such cases should be closely monitored and the extent and the mechanism should be explained.

• Commercial potential for vaccines in Europe

  Commercial companies in the field are interested. However, the development should be directed to new vaccines inducing broader protection, via subunits or new technologies.

  GAP:

  There is an urgent need for an update of the existing vaccines and development of new generation vaccines.

• Regulatory and/or policy challenges to approval

  Recently published EFFSA opinion on PRRSV categorisation within a framework of the Animal Health Law defines PRRS as eligible to be listed for Union intervention.

  GAP:

  A strategy for PRRSV control in the EU.

• Commercial feasibility (e.g manufacturing)

  The inactivated vaccines should contain higher amounts of viral antigens in order to be more effective. Until now, it has not been possible to develop an inactivated vaccine that can induce antibodies in such a quantity that can block the virus.

  GAP:

  Cell lines that allow higher production of PRRSV should be available.

• Opportunity for barrier protection

  Not available.

  GAP:

  One should consider this.

• Opportunity for new developments

  Specific and sensitive bedside blood tests for antigen/antibody detection are much-desired.

  GAP:

  Specific and sensitive bedside blood tests for antigen/antibody detection are much-desired.

• Pharmaceutical availability

• Current therapy (curative and preventive)

  None, only prevention of bacterial co-infections. Some effectiveness of tilmicosin in reducing PRRSV replication in vitro and the level of viremia in vivo was reported.

  GAP:

  No specific antivirals available.

• Future therapy

  A certain leukocyte population (X) is very active in eliminating PRRSV infected macrophages. Efforts should be made to identify this cell type and to better understand how to activate it.

  GAP:

  Identification of the effective leukocyte population X that can eliminate PRRSV infected macrophages.

• Commercial potential for pharmaceuticals in Europe

  New generation DIVA vaccines inducing universal protection would have incredible potential.

  GAP:

  New generation DIVA vaccines.

• Regulatory and/or policy challenges to approval

  None necessary at this moment

• Commercial feasibility (e.g manufacturing)

  Companies are very interested, although the limiting knowledge and the specific virus characteristics make it difficult to offer new alternatives.

  GAP:

  Independent research groups should help in the development of new generation vaccines and therapies.

• Opportunities for new developments

  Incorporation of PRRS testing into bedside tests would be useful especially micro-arrays for a variety of systemic diseases.

  GAP:

  Rapid PRRS testing in the farm can be a useful tool for diagnosing outbreaks.

• New developments for diagnostic tests

• Requirements for diagnostics development

  Necessary to monitor new genetic sequences to make sure that they are detected in the existing PCR/ELISAs. This requires isolation, whole genome sequencing and antisera production.

  GAPS:

  • PCRs/ELISAs should be continuously validated and updated with the appearance of new PRRSV isolates.
  • New and easy sampling methods to reduce managing of animals.
  • The new pan-European PRRS database would allow simultaneous comparison of PRRS isolates representing most countries in Europe.

• Time to develop new or improved diagnostics

  Continuous process that needs to be funded by EU or State initiatives.

• Cost of developing new or improved diagnostics and their validation

  In the range of other PCRs and ELISAs.

• Research requirements for new or improved diagnostics

  Surveillance is sufficient

• Technology to determine virus freedom in animals

  Would be very useful.

  GAPS:

  • More info on mechanism of persistence.
  • Is it possible to determine infection in persistently infected animal?
  • Diagnostic criteria for herd freedom from PRRSV

• New developments for vaccines

• Requirements for vaccines development / main characteristics for improved vaccines

  More fundamental knowledge on virus-macrophage interaction (receptors, disassembly, viral ligands) and virus-host interaction (active immune responses, immune evasion, virulence factors) is essential to develop an effective new generation of adaptable vaccines.

  GAPS:

  • Insufficient knowledge on virus-macrophage and virus-host interactions.
  • New vaccines should be safe, induce universal protection and marked.

• Time to develop new or improved vaccines

  As for other vaccines.

• Cost of developing new or improved vaccines and their validation

  As for other vaccines.

• Research requirements for new or improved vaccines

  1° better knowledge on virus-macrophage interactions (receptors, disassembly, viral ligands).

  2° better knowledge on virus-host interactions (active immune responses, immune evasion, virulence factors).

  3° development of fully susceptible cell lines to grow vaccine virus in order to increase the antigen load in vaccines and to improve the immune responses.

  4° Identification of the immune correlates of protection.

  5° Identification of leukocyte population that is able to eliminate PRRSV-infected cells and examine how to stimulate this cell.

  6° Identification of the impact of live PRRSV (attenuated or not) on the innate immune response of pigs.

  7º Identification of the potential spectrum of circulating strains covered by a given vaccine product (protectotypes).

  GAPS:

  • Insufficient knowledge on points 1°, 2°, 3°, 4°, 5°, 6° and 7°.
  • Identification of the complete set of immunogenic structural subunits that are required for establishing of an effective protective immunity.
  • Finding the basis for broadening the protective response.

• New developments for pharmaceuticals

• Requirements for pharmaceuticals development

  Development of antivirals

• Time to develop new or improved pharmaceuticals

  As for other antivirals

• Cost of developing new or improved pharmaceuticals and their validation

  As for other antivirals

• Research requirements for new or improved pharmaceuticals

  Full knowledge of virus replication in macrophages.

Disease details

• Description and characteristics

• Pathogen

  Porcine reproductive and respiratory syndrome virus (PRRSV) is a small, enveloped virus with a positive sense, single-stranded RNA genome. Until 2018 PRRSV was divided into two genotypes, PRRSV-1 and PRRSV-2, sharing only 55-70% of similarity at the genome level. According to the newest, revised classification of the International Committee on Taxonomy of Viruses (ICTV, Virus Taxonomy: 2018 Release), previous genotypes are now considered two distinct species named Betaarterivirus suid 1 and Betaarterivirus suid 2 and classified within two different Subgenuses (Family Arteriviridae, Suborder Arnidovirinae, Order Nidovirales).In the present document, commonly accepted and recognized traditional names (PRRSV-1 and PRRSV-2) will be used.

• Variability of the disease

  Previous classification differentiated two genotypes of PRRSV: PRRSV-1 (the European, Type 1, genotype I) with Lelystad as the reference strain) and PRRSV-2 (American, Type 2, genotype II) with VR2332 as the reference strain. Current classification of the ICTV acknowledged large genomic and antigenic differences between PRRSV-1 and PRRSV-2, and distinguished them as two different virus species (Betaarterivirus suid 1 and Betaarterivirus suid 2). PRRSV harbours significant and increasing genetic variability, due to frequent mutations and recombination events. Within each species, a large variation exists, leading to further subdivision into subtypes/clades/lineages. PRRSV-1 is further subdivided into three subtypes 1, 2 and 3, and there are evidences for the existence of at least one more (tentative subtype 4). The occurrence of subtypes 2, 3 and 4 seems to be restricted to the Eastern Europe while all strains of PRRSV-1 detected in the Central and Western Europe belonged to subtype 1. In the late eighties and early nineties, PRRSV-1 (previously descried as the European genotype) was restricted to Europe. PRRSV-2 (previously the American genotype) was circulating in America and Asia. Due to the use and spread of PRRSV-2-based vaccine in Europe as well as movement of infected pigs in between continents, mixtures of both species are present on all continents nowadays. Nevertheless, PRRSV-1 is the most prevalent in Europe, and PRRSV-2 dominates in America and Asia.The clinical outcome of PRRSV infection is very different in between strains, from lack of any clinical lesions to increased mortality in all age groups. Within both species, strains of higher pathogenicity were identified, including PRRSV-2 strain causing Sow Abortion and Mortality Syndrome (SAMS) in North America, High Pathogenic PRRSV (HP-PRRSV) associated with High Fever Disease (HFD) in Asia, or the PRRSV-1 strains of subtypes 3 (LENA, SU-1Bel), subtype 2 (Bor59) as well as subtype 1 strains e.g. strain Flanders 13 from Belgium and AUT15-33 from Austria. The emergence of high pathogenic variants indicates that relatively low virulent strains may undergo mutations significantly increasing their pathogenicity, like in the case of HP-PRRSV.

  GAPS :

  • Most often ORF5 was used for sequencing and estimation of phylogenetic relationships between strains. Due to frequent recombinations this approach is no longer sufficient. Whole genome analysis should be made in order to obtain correct genetic trees. These trees will be very important in epidemiological studies (evolution), pathogenesis research (pathogenicity, virulence, immune evasion) and immunological analysis (identification of B- and T-cell epitopes, vaccine development). In this context it is important to understand which parts of the genome are linked with a potential to spread, pathogenicity, virulence, immune evasion and immunogenicity.
  • Genetic and antigenic drift rates and forces influencing the selection or predominance of given viral variants should be investigated.
  • Mechanisms of increasing the clinical outcome after co-infections of PRRSV with other viruses, bacteria and toxins.
  • Role of recombination in PRRSV evolution and pathogenic strains emergence.

• Stability of the agent/pathogen in the environment

  The virus is transmitted horizontally (direct contact, contaminated fomites, airborne, via semen) and vertically (mainly after 70 days of gestation). Indications exist that the replication and transmission power of PRRSV in the respiratory tract is linked with the potential to spread airborne. PRRSV is inactivated easily by heat and drying. The virus is stable in an aerosol at low temperatures. At 4 °C, 90% survive for 1 week. At 56 °C, survival lasts only 6-20 minutes. The virus is stable at pH6-7.5 and can survive in muscle for a week at 4°C. It is quickly inactivated in a dry environment. In moisture it survives much longer (e.g. in a well water for 8 days and tap water for 17 days).

  GAP:

  The precise (quantified) role of fomites (i.e. trucks, boots) and of airborne spread , that seems to be dependent of the virulence or replication rates of each strain, are not known for genotype I strains. The precise role of airborne transmission is unclear as some evidences indicate differences among strains and an important influence of climatic conditions.

• Species involved

• Animal infected/carrier/disease

  Infects all pigs, including wild boar and feral swine

• Human infected/disease

  No evidence of any form of human disease

• Vector cyclical/non-cyclical

  No biological vector, but can be carried mechanically by arthropods from infected animals/farms to uninfected animals/farms.

• Reservoir (animal, environment)

  It is present in most pigs unless an eradication policy has removed the virus. Wild boar and feral swine form a wild reservoir. PRRSV infection in wild boars have been confirmed in several countries, including Italy, Germany, France, Slovakia, Croatia and Lithuania as well as in United States. The detection of vaccine-like strains of PRRSV circulating in wild boars suggests the direction of transmission from domestic pigs to wild boars. On the other hand, in Lithuanian wild boars strains from subtypes 3 and 4 of PRRSV-1 were detected, while in pigs only infections with subtype 2 are present. It was suggested that the wild reservoir in Eurasia harbours a huge variation of PRRSV strains and that escapes from this reservoir to domestic animals (removal of the iron curtain, migration/illegal transport of wild boar/feral swine & contacts with domestic animals) caused introductions of PRRSV in naïve populations or new types in immune populations.

  GAP:

  The situation in wild boar and feral pigs in Eurasia and the relevance of wild boars as a reservoir should be clarified.

• Description of infection & disease in natural hosts

• Transmissibility

  PRRSV can be transmitted by different routes, such as intranasal, intramuscular, percutaneous, oral, intrauterine and vaginal. Infectious PRRSV is highly present in nasal and pharyngeal secretions and theses fluids cause horizontal transmission in between animals (direct contact and airborne). Infectious virus is also present in semen and causes transmission in between boars and sows during insemination. Persistent shedders exist causing long term infections in herds. A lot of debate is going on concerning the minimal number of infectious virus that is necessary to cause infection. The minimum infectious dose differs by the route of exposure, being the percutaneous the one with lowest minimum infection dose. Also the virulence of the strains used may be of importance. As pigs are very susceptible to percutaneous exposure, routine husbandry practices such as teeth clipping or tail docking are very risky. With regards to indirect transmission, PRRSV can be transmitted via contaminated fomites, oral or blood samples, clothes, infected needles and insects such as flies and mosquitos. Transmission by aerosols has also been demonstrated, although it seems to depend on the replication capacity of the strain and environmental characteristics such as low wind and high relative humidity. PRRSV can also be transmitted vertically from sows to foetuses, as virus can cross the placenta efficiently from day 70-80 of gestation.

  GAPS:

  • Minimal amount of infectious virus necessary to cause infection depending on different strains and different routes.
  • The role of persistent shedders.
  • R value (different strains, impact of vaccination). Some info is available, but only of some strains and some vaccines.
  • Potential of vaccinated and later infected pigs for transmitting the virus to other naïve or vaccinated pigs needs to be assessed. Some info is available, but only of one vaccine.
  • The proportion of virus introductions that occur by each route in different epidemiological scenarios.

• Pathogenic life cycle stages

  The virus replicates in cells of the monocytic lineage (mø), mainly after differentiation. A range of cellular receptors including heparan sulphate, vimentin, CD151, CD163, sialoadhesin (CD169), DC_SIGN (CD209) and non-muscle myosin heavy chain 9 (MYH9) mediate virus entry, internalisation and uncoating processes. Sialoadhesin (Siglec, CD169) is an important but not essential receptor for binding and internalisation of PRRSV. CD163, a pH drop and proteases are involved in the disassembly of PRRSV. CD163 is indispensable for efficient infection, as CD163 knockout pigs are resistant to infection with PRRSV.Upon oronasal inoculation, the virus replicates in local mø of the respiratory tract and upon drainage, the virus replicates in draining lymph nodes. Efferent lymph is bringing cell free virus into circulation. The duration of viremia varies depending on the PRRSV strain and on the age of the animal (younger animals tend to have longer viremia). In general the period of viremia may range from a few weeks (usually less than 4 weeks) in adults or grower-finishers to up to 3 months in very young piglets. In sows, viremia is shorter, and could be of less than one week, especially if the immune system had been previously stimulated. Nevertheless, some studies have been able to detect viral RNA in serum at 251 days post infection. During viremia, the virus reaches internal mø concentrated in internal lymphoid tissues and disseminated in other organs. The virus also replicates in the endometrium and fetal placenta, causing a transplacental spread and fetal infection, mainly after 70 days of gestation.Upon infection in the testicles and secondary glands of boars, the virus is present in semen. Virus replication, as well as viremia and shedding post challenge, are most intensive in young piglets and in some animals virus may persist. The lungs and the lymphoid organs are the tissues with the highest viral loads in the initial phase. In lungs the virus is usually detected from 1-day post-exposure until 28 days post infection, although it has been found until 49 days post-exposure in young pigs. Lesions develop and depend on the pathogenicity of the strain, the age of infection, concurrent infections (bacterial and viral), host genetic factors and environmental stressors. Some breeds of pigs are more resistant to experimental infections than others. PRRSV replication mainly causes interstitial pneumonia and placentitis.

  GAPS:

  • Although PRRSV research has already solved several aspects of the virus-target cell interaction, huge gaps are remaining in the understanding of the replication (receptors, disassembly, transcription and translation, assembly and release).
  • Pathogenesis of the reproductive problems.
  • Mechanism of virus persistence and pathogenicity.
  • Identification of type of infected cells (macrophages, dendritic cells and subsets to which they belong) in lymph nodes and other lymphoid tissues in non-viremic stages.
  • Individual and/or genetic resistance mechanisms.

• Signs/Morbidity

  A variety of clinical syndromes have been described from subclinical to high morbidity/mortality (up to 30-50% with highly virulent strains). They may last 3 months or longer (especially when naïve animals are introduced) until they settle down. Once infected, herds tend to remain so, especially large or closed herds, as there is a continuous presence of susceptible pigs (young piglets, naïve replacement gilts). In continuous systems the problems are worse. In naïve herds, systemic signs may include anorexia, fever, depression, dyspnoea, discolouration of the skin (cyanosis), hyperaemia and anaemia. In sows some may show anorexia, fever, hyperaemia and congestion, ataxia, agalactia. Due to negative impact of PRRSV on the immunity, other endemic diseases may become more overt than before. Sow’s mortality can also be observed, mainly after infection with PRRSV-2 strains.

  • In neonates, there is a high pre-weaning morbidity and mortality, with ill-thrift and respiratory signs (hyperpnoea, dyspnoea). Diarrhoea may occur. Also splaylegs can be observed. Upon co-infection with Streptococcus suis nervous disorders may be seen.

  • In weaning or growing pigs, characteristic signs include anorexia, lethargy, dyspnoea (thumping) hyperaemia, peri-orbital oedema, and anaemia. In many instances you find Glasser’s disease and Streptococcal infections as the cause of death. Average Daily Gains are also negatively affected.

  • In sows, late-term reproductive signs may be observed including abortions and premature farrowing/early farrowing from 100 days onwards (sometimes up to 20-80% of sows) during an acute outbreak. The affected litters may have partially mummified (brown, late-term deaths), stillborn and weakly born piglets. Between 0-100% of the litters may be affected. Delayed oestrus, excessive returns to service and low conception rates may be observed. In the Sow Abortion Mortality Syndrome (SAMS) associated with specific USA isolates, the normal 1-3% level of abortion may increase to 10-50% and the mortality rate may reach 100%.

  • Boars may be ill (anorexia, lethargy, and respiratory signs) and there may be lack of libido and sperm abnormalities for up to 10 weeks post-infection.

  In both species strains of higher pathogenicity were identified (e.g. PRRSV-1 subtype 3 strain LENA and PRRSV-2 Asian HP-PRRSV), with the clinical outcome much more severe and morbidity reaching up to 100%. In conventional animals mortality may easily reach 30-50%.

  GAPS :

  • How is PRRSV exacerbating the outcome of other infections.
  • Why are some PRRSV-2 (HP-PRRSV) and PRRSV-1 (LENA) strains damaging the immune machinery more aggressively?
  • What is the basis of virulence/pathogenicity.
  • How to predict the virulence of a field strain.
  • Role of co-infections, especially regarding antibiotic use and the problem of the induction of antibiotic resistant bacteria.

• Incubation period

  Usually 1-7 days in experimental infections with a spread taking one to several weeks.

• Mortality

  Mortality is strain dependent, ranges from 0-50%, may be higher in naïve herds infected with high pathogenic strains.

  GAP :

  Why ?

• Shedding kinetic patterns

  After viremia, virus can be isolated from different tissues for different periods of time: oropharyngeal scrapings until 157 days post infection (dpi) and tonsils 150 dpi.Viremia and virus distribution leads to shedding via nasal secretions, saliva, urine, faeces, mammary gland secretions, and semen.

  Nasal shedding seems to be strain dependent. In case of PRRSV-1 it can be detected until 48 dpi, and with PRRSV-2 - until 38 dpi intermittently. Shedding in faeces is irregular.Shedding in oral fluids seems to be more constant. Oral fluids were found positive by RT-PCR from 3 dpi to 4–5 weeks post-inoculation in some studies. Shedding in semen ranges from 3 to 92 dpi intermittently. PPRSV can be also shed in urine and mammary gland secretions, although this last route of transmission is probably not very relevant.A fraction of the animals are persistently infected and may contribute to maintaining virus circulation in the herd. The observation of the same virus reappearance in infected sow 500 days after primary infection in a stabilised, virus-negative sow herd indicate that duration of persistence might be underestimated. Stress situations can reactivate viral replication and it had been demonstrated after 15 weeks since initial infection.After a few months a PRRSV infection wave results, in the best scenario, in a population immunity that might block further circulation (stable herd). Upon time and frequently upon introduction of negative gilts (naïve subpopulation) the herd may become reinfected by the persistently infected sows, leading to problems again (unstable herd). This leads to periods of stability and unstability. Stabilization of a farm, and mainly the maintenance of this stable situation in time, is a difficult task that includes multifactorial approach, with immunization of the animals (via vaccination or natural infection following the herd closure), management, biosecurity and monitoring. Although vaccination of sows and piglets is not enough to prevent infection, it helps to reduce clinical signs, viremia, shedding and virus transmission. Nevertheless, protection is not complete nor universal for all the strains. In some countries, farmers try to stabilize their herd by infecting naïve replacement gilts with the virus that is present on the farm. This is a risky approach that is in clearly disuse because of its safety concerns.

  GAPS :

  • What is the basis of the virus persistence? Why only in some pigs? Persistence of the virus in domestic pig should be thoroughly studied, since
  • How to determine the end of shedding
  • How to stabilize a herd
  • More research is necessary to have better insights in the circulation kinetics of PRRSV.

• Mechanism of pathogenicity

  The basis of pathogenicity and virulence are largely unknown. Damages of the cells of the monocytic lineage (mø), particularly in lungs and lymphoid tissues may in one way or another facilitate secondary infections. The mechanism is unclear. How PRRSV induces late term abortion/early farrowing is also not very clear (placentitis due to replication in CD163+ and Sn+ macrophages). Because PRRSV is only replicating in the cells of the monocytic lineage (mainly macrophages), it is difficult to explain that this is the reason of the death of the fetuses. Most probably, the replication of PRRSV in macrophages at the placenta may be the reason. However, more research should be done to have a better understanding.

  GAPS :

  • What is the basis of pathogenicity/virulence?
  • How does PRRSV negatively impact the immune response, in particular with regards to other pathogens, i.e. PCV2 and bacterial infections?

• Zoonotic potential

• Reported incidence in humans

  None

  GAP:

  It should be examined at what level the resistance occurs (binding to sialoadhesin, internalisation, disassembly, transcription, translation, assembly, release).

• Risk of occurence in humans, populations at risk, specific risk factors

  Not determined

  GAP:

  Due to homologies between human and pig macrophages, it should be examined at what level the resistance occurs (binding to sialoadhesin, internalisation, disassembly, transcription, translation, assembly, release). By doing this, the risk of infections in humans can be assessed.

• Symptoms described in humans

  None

• Estimated level of under-reporting in humans

  Not likely

• Likelihood of spread in humans

  None at present

• Impact on animal welfare and biodiversity

• Both disease and prevention/control measures related

  •PRRS control needs to be faced from a multifactorial approach, including immunization of sows and/or piglets, management procedures, internal and external biosecurity, and monitoring programmes. Combination of all these factors will help to stabilize sow’s herd. As protection induced by available vaccines is not total nor universal, it is necessary to focus also on management and biosecurity strategies to reduce viral presence and persistence in the farm. Nevertheless, recent studies have demonstrated the efficacy of some commercial vaccines in reducing PRRSV transmission in vaccinated populations, helping therefore to reduce virus infectious pressure in a farm or even a region (Ro<1).• In some countries (e.g. northern America) farmers infect their naïve replacement gilts with a field virus in order to give them the best immunity to protect them clinically. This practice, common years ago, is in clear deuse, mainly due to the clear safety limitations.• Depopulation/Repopulation is successful, however reinfections due to a new field strains introductions are frequent, and should be avoided with biosecurity measures• Semen should come from boars of PRRSV free artificial insemination centres.• Highly virulent strains may circulate aerogenic. In that context the use of air filters makes sense.

  GAPS :

  • Animals should be checked more thoroughly during import/export of animals. Controls by authorities are wishful.
  • Vaccines should be adaptable. Adaptable inactivated vaccines already exist. Efforts should be made to develop adaptable attenuated and vector vaccines.
  • Development of new vaccines that induce total and universal protection, marked vaccines, that could be differentiated from field infection.
  • More field work is essential to better understand the impact of vaccines. Marker vaccines and differential ELISAs would be ideal for doing this work.
  • Develop tools that could check the correct immunization of a vaccinated animal, as well as the degree of protection.
  • Role of MLVs in PRRSV evolution (persistence in the field, reversion to virulence, recombination with wild type strains).
  • Proper vaccination regime together with strict biosecurity measures must be applied, otherwise field virus evolution will accelerate due to vaccine induced selection pressure.

• Endangered wild species affected or not (estimation for Europe / worldwide)

  Endemic in all breeds of pigs. Rare breeds may be at risk if a SAMS or High Pathogenicity type of PRRS gets into the country.

• Slaughter necessity according to EU rules or other regions

  Not at this moment. However, the virus goes in the direction of full immune escape. Whenever this occurs, slaughter strategies should be considered.

  GAP:

  It is essential to control regularly the escape power of the circulating PRRSV isolates. A surveillance is essential.

• Geographical distribution and spread

• Current occurence/distribution

  Worldwide, although some countries are negative (Brazil, Sweden, Finland, Norway, Switzerland, Australia and New Zealand). Originally, PRRSV-2 circulated in America and Asia while PRRSV-1 circulated in Europe. Nowadays the occurrence of both PRRSV species has globalized. In Europe, the subtype 1 of PRRSV-1 is mainly circulating in central and western European countries. The occurrence of the subtypes 2, 3 and 4 is limited to countries that in the past belonged to the USSR. Higher diversity of PRRSV-1 strains from that region suggest that is was the area where the virus evolved, and later escaped to remaining European countries.PRRSV-2 strains detected in Europe are mainly of vaccine origin, however, wild-type PRRSV-2 strain of unknown origin was identified in Hungary. High Fever Disease virus is spread all over Asia.

  GAPS:

  • PRRSV-2 epidemiology in Europe.
  • Lack of comprehensive data on PRRS occurrence and prevalence as well as full spectrum of genetic variability of circulating strains.

• Epizootic/endemic- if epidemic frequency of outbreaks

  Within an enzootic situation, epidemics of highly virulent strains still may occur. Examples are High Fever Disease virus in Asia and Sow Abortion and Mortality Syndrome in the US. It is clear that certain high virulent strains can spread within an immune population. In Belarus highly virulent strains are circulating.

  GAPS:

  • PRRSV has the potential to increase its virulence in time. One should be prepared for this situation. At present Europe is not ready. There is no action plan prepared for the situation when a high virulent PRRSV appears in Europe.
  • Risk analysis and preparedness plan for the introduction and/or appearance of a highly virulent PRRSV strain in Europe including an economic evaluation of the potential impact.

• Seasonality

  Some reports from USA and Europe indicate that the frequency of new outbreaks is higher in the autumn/winter seasons. Some observations suggest regional difference in seasonal patterns. Most probably seasonality in PRRSV outbreaks is related with easier virus survival and spread within cold and damp environmental conditions.

  GAP:

  A better understanding of the pattern and causes of the PRRS seasonality would aid the implementation of more effective control measures for the disease.

• Speed of spatial spread during an outbreak

  Reproduction rate (Ro; the mean number of cases infected by one infectious case) of PRRSV differs depending on the species and the strain itself. Ro values for PRRSV-1 range from 2 to 5. There is not so much info for PRRSV-2 or subtypes 2 to 4 of PRRSV-1. Compared to other diseases, PRRS spread is not so rapid. Nevertheless, the constant movement of animals, the high density areas and the aerosol spread suggests that PRRSV spread can be moderately rapid.

  GAPS:

  • Identification of temporo-spatial patterns of dissemination tracing the circulation of PRRSV strains in an area.
  • Reproduction rate of PRRSV-2 and subtypes 2 to 4 of PRRSV-1.

• Transboundary potential of the disease

  PRRSV does not know boundaries

• Route of Transmission

• Usual mode of transmission (introduction, means of spread)

  Pigs can be infected by either direct contact or indirectly through fomites. Exposure to PRRSV occurs via respiratory, oral or mucosal route or percutaneously. The virus reaches an animal by direct contact, contact with infected secretions (direct or indirect iatrogenic), insemination or coitus, by ingestion, inoculation, or via aerosols.

  Vertical transmission: mainly after 70 days of gestation.

• Occasional mode of transmission

  Via insects (mechanically), airborne

• Conditions that favour spread

  * Like most viruses PRRSV is more stable in cold weather with no ultra-violet radiation.* Poor biosecurity measures:

  • Continuous pig movements (no all-in/all-out)
  • No control of transports, visits, materials, clothes, etc
  • No frequent change of needles
  • Closed herd production system
  • High pig density areas.

  * No air filtration.* Introduction of naïve gilts with no proper quarantine and adaptation program.* Use of contaminated semen.

  GAP:

  Quantitative identification of different routes of spread.

• Detection and Immune response to infection

• Mechanism of host response

  PRRSV immune response is slowly-developing and complex.The interferon alpha production is hampered as a result of interactions with viral proteins, mainly Nsp1, Nsp2, Nsp11and N. Antibodies appear late during the infection starting from 7 days post inoculation. These early antibodies are directed against the viral nucleocapsid, but have no role in protection. Neutralising antibodies appear within 4-5 weeks post inoculation and are mainly directed against GP3, GP4 and GP5 and eventually GP2. Their role in protection is unclear, and their induction is strain-dependant. Some strains induce very low or even no detectable levels of neutralizing antibodies.Cell-mediated immune response is also slow and takes 4-6 weeks or more to develop. Cell-mediated immune response is crucial for protection. There is a clear correlation between the amount of IFN-γ induced by a strain (field or vaccine) and protection. Cytotoxic T-lymphocytes are not able to kill PRRSV-infected macrophages. NK-cells are also hampered in their activity. PRRSV disturbs defence mechanisms to secondary infections.Mechanisms of immune evasion include display of decoy epitopes in the proximity of neutralizing epitope of GP5, glycan shielding of main envelope glycoproteins GP2 and GP3.

  GAPS :

  • There is a certain leukocyte type that can eliminate infected macrophages, but it is not yet characterized.
  • Refining of techniques for measuring the adaptive immune to PRRSV.
  • Nothing is known about the local immunity in the respiratory tract.
  • Mechanisms underlying the down-regulation of IFN-α have mainly been studied in vitro in “artificial” cell systems like HEK cells. In vivo studies or in vitro studies with relevant porcine cells are necessary for a better insight into the effect of IFN modulation.
  • How to predict the capacity of a strain to induce IFN-ɣ.
  • Which are the epitopes responsible of inducing IFN-ɣ and why there are differences between strains and individuals.
  • Identification of mechanisms of immunomodulation and immune evasion in PRRSV infection.
  • Lack of a good challenge model for PRRSV-1 and respiratory disease.

• Immunological basis of diagnosis

  For initial monitoring/diagnosis, a wide variety of ELISAs has been developed, most of them using recombinant nucleocapsid protein as an antigen (sometimes GP5) and capable of identifying antibodies directed to both PRRSV-1 and PRRSV-2 strains.In general, they have good specificity and sensitivity, however, single false-positive reactions may occur. In order to confirm the initial positive results in doubtful cases or differentiate PRRSV species, an indirect immunoperoxidase monolayer assay (IPMA) or indirect immunofluorescence (IIF) using alveolar macrophages and MARC-145 cells can be applied.

  GAPS :

  • ELISAs should be controlled for the detection of antisera directed against divergent strains, such as the LENA strain (PRRSV-1, subtype 3), especially considering high level of diversity within ORF7 region encoding nucleocpasid protein observed within Eastern European strains.
  • Differential ELISAs should be developed. In combination with new adaptable vaccines, a control/eradication strategy may be launched.
  • Techniques to measure protection should be developed.

• Main means of prevention, detection and control

• Sanitary measures

  •Introduction of negative replacement gilts and immunization (following a correct quarantine and adaptation schedule replacement animals should be vaccinated or exposed for infection with a herd strain).• Introduction of seropositive animals should be considered as a very high risk factor.• Introduction of replacement animals to a negative herd only after a quarantine and negativity confirmed with diagnostic tests.• PRRS-free artificial centres or control of semen.• Depopulation/Repopulation or other management protocols: herd closure and rollover, partial depopulation, test & removal, wean & removal.• Air filtration.• All in/all out.• McRebel management in farrowing units.• Cleaning/disinfection of contaminated stables and lorries.• Insect control.• Use of needle free devices or correct needle management• General external and internal biosecurity measures, including separate personnel in sow, nursery and fattening units.• Vaccination and biosecurity measures allow elimination from the sow herd and nursery. However, fatteners should be moved from the farm in order to prevent reinfection.

  GAPS:

  • PRRSV is extremely difficult to control by sanitary measures.
  • Identification of the most common routes of entry of PRRSV in pig farms.
  • Quantification of the number of new virus introductions per year in different areas and under different conditions and evaluation of the risk of re-introduction of the PRRSV infection.
  • Simulation programs that predict the risk of reintroducing PRRS on a farm depending on its individual characteristics (location, type of herd, biosecurity, management….).

• Mechanical and biological control

  • Disinfection is easy.• Air filtration is effective to keep airborne PRRSV out.• Introduction of seropositive animals should be stopped. Correct quarantine and adaptation of negative gilts should be established.• Use of negative semen should be mandatory.

• Diagnostic tools

  History, post-mortem examination, histopathology with immunohistochemistry, seroconvertion, seroprofiles, virus isolation and titration (viral load)/PCR with subsequent sequencing. Sequencing will add epidemiological information about the possible origin, evolution of the strain or the introduction of a new one. Routine monitoring of the negative herds can be done by serology on sera, oral fluid or technological fluids samples.The standards for PRRS diagnostic are summarized by the OIE in the Manual of Diagnostic Tests and Vaccines for Terrestrial animals.

  GAPS:

  • None of currently applied PCRs guarantees the detection of all isolates/strains. PCR methods should be constantly validated and updated toward new/divergent strains.
  • Regular pathological studies for new virus strains
  • New easy techniques for diagnostics should be checked, such as PCR on processing material (technological fluids), or lactating piglets oral fluids.
  • Diagnostic criteria for herd freedom from PRRSV.

• Vaccines

  Both attenuated live and inactivated vaccines are available, containing either PRRSV-1 or PRRSV-2 strains.Inactivated vaccines are safe but not efficacious, as it has been demonstrated that they cannot control viremia post-challenge by themselves. They can only boost the existing immune response in sows. Inactivated vaccines do not protect naïve animals and give only boost reactions when the animals have been previously exposed to field virus or MLV vaccines.Modified Live vaccines (MLV) vaccines have been proved to be able to reduce clinical signs, viremia and shedding post-challenge, as well as reduce virus transmission in vaccinated populations. With regards to safety, some level of limited horizontal and vertical spread can be found, as well as vaccine strain shedding. These characteristics differ between vaccine strains. Although initially it was assumed that efficacy of attenuated vaccines was depending on the homology of the field virus, it has been proved lately that this is not the only or the most important factor. The efficacy also depends on the capacity of the vaccine to induce cellular immunity and, probably, virus-neutralizing antibodies. Nevertheless, vaccine efficacy is always partial and usually lower towards heterologous strains. Therefore, there is an urgent need for new generation vaccines that could provide universal protection. Additionally, it would be highly appreciated to differentiate vaccinated animals from infected ones, so DIVA vaccines would also be desirable. To achieve this development, new approaches of vaccine production should be considered, such as multivalent vaccines or subunit vaccines. Commercial companies in the field are interested but there are no vaccines available that induce universal protection. Therefore, there is an urgent need for a new generation vaccines.

  GAPS:

  • More effective vaccines, ensuring universal and total protection, safe and marked.
  • Better knowledge of protective immune responses - identification of common protective epitopes, epitopes that induce neutralizing antibodies and leukocytes that are effective in eliminating infected macrophages.
  • Better knowledge of the viral components that are linked with pathogenicity/virulence. Identification will allow an oriented development of attenuated vaccines by reverse genetics.
  • Mechanisms and criteria of cross protection
  • Identification of strains that give the highest cross protection.

• Therapeutics

  None except support therapy in young pigs preventing co-infections with PCV2 or bacteria.Some reports indicate the effectiveness of tilmicosin in reducing PRRSV replication in vitro and the level of viremia in vivo.

  GAP :

  No antivirals are available

• Biosecurity measures effective as a preventive measure

  Full external and internal biosecurity is essential but is not easy to accomplish. Also because of an aerosol spread, it cannot guarantee the 100% effectiveness unless all buildings have incoming air filters.

  GAP:

  Development of biosecurity assessment protocols suitable for PRRS control.

• Border/trade/movement control sufficient for control

  Clinical inspection may suggest illness, but subclinical infections occur. No other possibilities exist at this time until bedside ELISA tests are fully developed. Quarantine of imported animals is advised, in combination with laboratory confirmation of negative status. More detailed recommendations are listed in the OIE Terrestrial Animal Health Code, Chapter 15.3 “Infection with porcine reproductive and respiratory syndrome virus”.

  GAPS:

  • Unified protocols of quarantine and diagnostic testing of imported animals.
  • Quick penside diagnostic tests

• Prevention tools

  Individual farms and companies strive to control disease by immunizing sows (vaccination at 60 days of gestation and 6 days of lactation, or mass vaccination every 3-4 months; controlled infection/immunisation of gilts) and piglets. Previously available vaccines were considered unable to eradicate PRRS, however, it has been demonstrated that some vaccines reduce virus transmission rate (a reproduction rate R<1), being suitable for eradication programs. There are documented experiences of eradication based on combined vaccination, management and biosecurity strategies. Also depopulation/repopulation strategies are used to get rid of PRRSV. However, reinfections may occur quite commonly with disastrous outcome.

  GAP:

  Strategies to eradicate PRRSV by the use of marker vaccines/differential ELISAs are not developed.

• Surveillance

  It is essential to maintain surveillance. In general, there is a lack of official information about PRRS prevalence, as the control of this disease in not mandatory. It is essential to know the prevalence of the disease in sows, weaners and finishers, and also which strains are present in certain regions and if the available vaccines are inducing sufficient immunity. Mutations or introduction of foreign strains may be disastrous for pigs (health, food security, economical problems).In the course of eradication programme, bulk tonsil samples of culled sows can be checked by PCR.

  GAPS:

  • There is no coordination in the surveillance and control of PRRSV. Europe is waiting for the day that strains with higher virulence appear. Tools should be developed to prepare for such a scenario.
  • Feasibility of clinical passive surveillance systems and databases should be examined (early alert for highly virulent strains).

• Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

  Vaccination with MLV vaccines have been demonstrated to be effective in reducing clinical signs, viremia, shedding and virus transmission. There are also a lot of success experiences where combining vaccination of sows and piglets and management and biosecurity measures allowed for PRRS control and sometimes complete eradication from a farm.Nevertheless, this is more difficult to be achieved in big farms, closed herds or herds located in very high pig density areas. Additionally, mainly in high density regions, reinfections are common, so it is difficult to keep a PRRSV-free herd status.Currently national surveillance/eradication programme is implemented in Hungary, and, outside of Europe, in Chile, which previously eradicated PRRS and in 2013 suffered re-infection. Some regional programs were undertaken in several countries with promising results (USA, Denmark, The Netherlands, others). Reports of fast PRRS eradication after introduction into free-status countries (Sweden, Switzerland) identify the immediate mobilization of veterinary authorities, field veterinarians and the pig industry as critical factors preventing the spread of the disease.

  GAPS:

  • Better vaccines should be developed. Because PRRSV is genetically drifting, the efficacy of vaccines should be controlled in time.
  • Development of vaccines that induce universal and total protection.
  • Lack of organized control efforts and policy regulating PRRS control.

• Costs of above measures

  Every farm is spending money to control PRRSV (depopulation/repopulation, semen control, diagnosis, vaccination, air filtration, biosecurity, …). A comprehensive analysis for the costs of biosecurity activities and vaccination programmes is lacking.

  GAP:

  Return of Investment studies.

• Disease information from the WOAH

• Disease notifiable to the WOAH

  Yes

• WOAH disease card available

  No.

• WOAH Terrestrial Animal Health Code

  http://www.oie.int/index.php?id=169&L=0&htmfile=chapitre_prrs.htm

• WOAH Terrestrial Manual

  http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/3.08.06_PRRS.pdf

• Socio-economic impact

• Zoonosis: impact on affected individuals and/or aggregated DALY figures

  Worldwide, farmers that are confronted with PRRS problems, caused by high virulent PRRSV or PRRSV that escapes from the vaccine immunity, are faced with economical losses.Severe economic loss until disappearance of clinical signs and sow stability occurs

• Zoonosis: cost of treatment and control of the disease in humans

  None

• Direct impact (a) on production

  This disease is the most important endemic pig disease causing continuously negative impact on health and welfare of piglets and sows and production losses. During outbreaks of high virulent PRRSV, large losses are reported (30-50% of mortality). When high virulent strains remain on a farm (endemic situation), mortality remains high in the nursery unit.A small-scale study performed in The Netherlands estimated that in an acute reproductive outbreak, cost of PRRS reaches € 59-379 per sow. In endemic situation, the cost varies from € 3 to 160 per sow. In growing animals, the cost is very variable, moving from € 1.6 to 7 per piglet.The total impact on production is not known. It was estimated for US $ 664 million annually in USA.

  GAP:

  Knowledge on financial impact of PRRS is limited.

• Direct impact (b) cost of private and public control measures

  • Vaccination costs• Serological survey/ diagnosis costs• Costs to create and maintain a PRRSV free artificial insemination centre.

  GAP:

  Knowledge of financial impact is limited.

• Indirect impact

  Loss of production increases price of finishing pigs to the farmer and reduces the income of farmers.Because co-infections of PRRSV with bacteria result in aggravation of the clinical outcome, antibiotics are used in large amounts. The extensive use of antibiotics during PRRSV-bacterial co-infections may induce resistance which forms a danger to a public health.In Asia, the appearance of the PRRSV High Fever Disease led to a mortality of 30-50 % in pigs and caused problems with the security of food supply.

  GAP:

  Knowledge of financial impact is limited.

• Trade implications

• Impact on international trade/exports from the EU

  Only countries considering themselves free (Sweden, Finland, Norway, Switzerland, Brazil, Australia and New Zealand) will not accept pigs. Some restrictions are expected in transport to countries having an open control program for PRRS (Chile, Hungary). In most of other countries PRRS remains endemic.The OIE gives general recommendation to prevent transboundary transmission of PRRS via international trade in the Terrestrial Animal Health Code (Chapter 15.3).

• Impact on EU intra-community trade

  None at this moment, except for some import restrictions to the countries free from PRRS (Switzerland, Sweden, Norway, Finland) or Hungary, where national control program is implemented.

• Impact on national trade

  None at this moment. Only measures on a free basis.

• Main perceived obstacles for effective prevention and control

  Farmers perceive PRRS as the most important disease in pigs.The virus is genetically on the move. As PRRS vaccines are offering partial protection only, success of control programs depends also on other factors such as management and biosecurity. These factors are not always easy to handle, which causes some impotence about PRRS control. Farmers doubt on the efficacy of the vaccines. Farmers fear the appearance of high virulent PRRSV. No comprehensive and infallible strategy to control PRRS was developed.

  GAPS:

  • DIVA vaccines.
  • Virus evolution monitoring.
  • Exact costs-benefits estimation of PRRS control measures could convince farmers to implement control measures.

• Main perceived facilitators for effective prevention and control

  EU directives, State Health Services, farmer organisations, private or company veterinarians, pharmaceutical industry, drug agencies.

  GAP :

  Common policy and coordinated efforts for PRRS control.

• Links to climate

  Seasonal cycle linked to climate

  Some reports from USA and Europe indicate that outbreaks are more common in autumn and winter months, most probably due to the higher virus stability during those seasons.

  GAP :

  More studies about seasonal activity should be done.

• Distribution of disease or vector linked to climate

  PRRSV survives better when in low temperature and high humidity, therefore the frequency of outbreaks may be higher in the autumn and winter.

• Outbreaks linked to extreme weather

  As stress can activate virus shedding in persistent infected animals, extreme heat stress could favour outbreaks.

• Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

  Not known

Risk

• Rapid mutation may result in a high virulent PRRSV, that destroys pig population in a very short time (similar scenario took place in China after the emergence of the High Pathogenic PRRSV).

  GAPS:

  • Monitoring of the population.
  • Determination of the basis of virulence.
  • Adaptable vaccines.

Conclusion

• PRRSV is one of the most important infectious pig pathogens nowadays. A high mutation rate is problematic for diagnosis and future control of PRRS. High virulent strains may emerge and PRRSV mutants may be difficult to control by the registered vaccines. Farmers should be informed about the impact of PRRSV infections in their herds and should be helped to control PRRSV circulation.

  GAP:

  Many knowledge gaps exist.

Sources of information

• Expert group composition

  Katarzyna Podgórska, National Veterinary Research Institute, Poland – [Leader]

  Marta Jiménez, MSD

  Ádám Bálint, National Food Chain Safety Office Veterinary Diagnostic Directorate, Hungary

  Tomasz Stadejek, Warsaw University of Life Sciences, Poland

• Reviewed by

  Project Management Board

• Date of submission by expert group

  3 April 2019

• References

STAR-IDAZ Research Road Maps

• PRRS Vaccine Development