NC229: Detection and Control of Porcine Reproductive and Respiratory Syndrome Virus and Emerging Viral Diseases of Swine
(Multistate Research Project)
NC229: Detection and Control of Porcine Reproductive and Respiratory Syndrome Virus and Emerging Viral Diseases of Swine
Duration: 10/01/2014 to 09/30/2019
Statement of Issues and Justification
History of the groups activities and its outcomes: Rationale for renewing this project for the period 2014-2019
Started in 1999, the newly formed NC 229 Multistate Committee first addressed the topic Porcine Reproductive and Respiratory Disease Syndrome: Methods for the integrated control, prevention and elimination of PRRS in United States Swine Herds. Since its very onset, the group has used a novel "consortium" approach to pursue stakeholder-driven major scientific goals on the virology, immunology, epidemiology, diagnostics and control of PRRSV, combining National Pork Board (NPB), industry and USDA funds.
Close to a decade later (on November 2008, and just on the eve of its third and most recent renewal), the NC 229 Committee was awarded the first annual Experiment Station Award for Excellence in Multistate Research by the Experiment Station Committee On Organization And Policy, conferred by The Board on Agriculture Assembly, of the National Association of State Universities and Land-Grant Colleges. The NC229 committee was commended because (sic) it has been a model of multistate collaboration between institutions, working with stakeholders and providing leadership in partnering with private organizations such as swine breeding companies, diagnostic and vaccine companies and the National Pork Board. This committee is very connected to stakeholders in the swine industry and stakeholder concerns are addressed in the objectives of this project. The main reasons for such noteworthy distinction can be summarized as follows:
Throughout its existence, the NC-229 Multistate Committee has consisted of an important body of researchers that provides a forum for discussion and think-tank capabilities essential to coordinate strategies towards the control of PRRS and other major emerging diseases of swine, for example:
" The NC-229 group of researchers has been the main driving force for the preparation and successful award of an initial USDAs Coordinated Agricultural Project (CAP) in 2004-2008, which, following its renewal in 2010, led to the overall record achievement of almost $10 million dollars available for research, extension and education in PRRS and related diseases. The extraordinary significance of the NC-229-originated PRRS CAPs I and II , becomes clearly evident when it is taken into account that, combined with Check- off funding provided by swine industry (NPB), brought a total dedicated to PRRS research to more than $20 million dollars distributed for creative research and extension within the last ten years.
" The NC-229 scientific meetings offered the appropriate forum and the foundation for the organization of an Annual PRRS Scientific Symposium that, although initiated first at a national level, quickly became a yearly event of major international scope known as the International PRRSV Symposium. To this end, the basic scientific organizational capacity of NC-229 was energized and materialized thanks to the financial backing secured through the CAP funds and also through support received from the swine, pharmaceutical and biologics related industries.
" Since the initiation of this multistate committee, the NC-299 participants formed an important critical mass of collective expertise that nurtured numerous advisory cadres in charge of contributing knowledge for scientific panel reviews and policy-making recommendations on swine health to the NPB, USDA, academia in general and swine producers and veterinarians, both nationally and internationally .
Upon its most recent renewal in 2009, the NC-229 group expanded its goals beyond the topic of PRRSV to include other important swine emerging diseases. These additional important topics became an integral part of the program of annual symposiums of the NC-229 group, and proved to be of critical importance for those moments involving critical decisions or conclusions, such as the successful realization that porcine circovirus associated diseases (PCVAD) can be controlled by effective vaccination, the identification/characterization of swine influenza isolates of importance to public health, and most recently, the identification and quick adoption of diagnostic tools and appropriate disease management know-how to face the ongoing outbreak of porcine epidemic diarrhea virus (PEDV). The latter disease is now a reality faced by US swine producers, although it had been considered, until as recently as May 2013, just one more exotic disease to North America. Unfortunately, that is not the case anymore(3).
As we will exemplify in the following paragraphs, the overriding economic importance of PRRSV to North American agriculture, plus the significance of other emerging diseases represented for example by the permanent concern posed by swine influenza, the actual domestic threat presented by PEDV or the potentially very serious hazard represented by the presence of ASFV at the very doors of Europe and the Western Hemisphere(4), justify the continuation of this NC-229 multistate project. The intriguing and complex field of emerging viral diseases of swine surging and expanding in a planet with an ever-globalized economy does not allow us to let our guard down. Therefore, the title of Detection and Control of Porcine Reproductive and Respiratory Syndrome Virus and Emerging Viral Diseases of Swine for this multistate project, has been very appropriate.
The need as indicated by stakeholders:
PRRS continues to be the most devastating disease of swine in the USA. While important advances have been achieved in control of this disease, some important obstacles still exist due to the unique immuno-pathogenic characteristics of this virus. Successful completion of the NC-299 project aims will undoubtedly result in enhanced control of PRRS. Benefits will include reduced animal suffering, thus enhancing health and well-being. Swine producers will experience improved economic gain due to reduction in animal losses and more efficient pork production.
At the time the NC-229 2009 renewal was being submitted, the swine industry remained burdened with the staggering $560-million price tag for production losses associated with PRRS calculated in 2005(5). Since the previous economic study was released, and despite important advancements in research and production schemes, the cost of this disease continues to rise. A team led by Iowa State researchers recently completed a year-long study of the economic impact of the virus on the pork industry (7). The new study, which is in the process of being published by NPB and several industry web sites, estimates the total tab to the industry at $664 million annually, based on a review of production records from 80 breeding herds and grower pig closeout data on more than 600 groups of pigs over the past 3-5 years. Most importantly, the current analysis also includes expert opinions from more than 26 swine veterinarians who provide services to 2.4 million U.S. sows, which roughly represents 45% of the nations sow herd. In addition, based on these experts opinion survey, animal health costs tack on another $140 million annually due to PRRS. The annual biosecurity and other outbreak-related costs attributed to PRRS were estimated to be $191.86 million and $145.82 million, respectively. Biosecurity costs include installation of air filtration systems, truck washes and other changes to transportation, added showers, changes in pig flow, etc. Total additional costs were pegged at $477.79 million annually, putting the cumulative cost of the disease at more than $1 billion/year when added to production-related losses(7).
Since its discovery in 1991, the PRRS virus has proven itself as a significant pathogen of swine in nearly all production areas of the world(2). In 2006 it became apparent that strains of extraordinary virulence had surfaced in China, causing a major blow to the worlds largest swine herd(10). This threat and the general concern about virulence exacerbation by intense genome mutations in the field has reemphasized the need for effective PRRS control and the importance of finding predictably successful tools for managing or eliminating the virus from farms. The NPB, for the last 8 years, has been engaged in PRRSV area control and elimination efforts through research and education efforts that support and continue to develop tools and strategies to better manage the virus. In 2013, the Swine Health Committee of the NPB developed the following statement to help guide PRRS research and outreach efforts: The short-term objective (ideally to be accomplished in less than 3 years) is to reduce the impact PRRS has on producers, and to assess the feasibility and financial acceptability of PRRS area control and/or elimination for producers. To that end NPB has identified the following 4 major focus points, which are mirrored in and consist of the foundations of the objectives of this current NC229 proposal(8):
1) PRRSv Immunity and Vaccinology: centered at understanding correlates of immunity and mechanisms to broaden protection
2) PRRSv Epidemiology and Surveillance: with emphasis in understanding virus transmission and differential testing of animals(DIVA) and
3) Economic Impact of Interventions: with emphasis at determining the economic benefit of vaccination in positive herds
The national priorities for swine health research established by NPB and American association of swine Veterinarians (AASV) constitute an accurate gauge of the stakeholder needs in the area of other emerging diseases of swine of interest for the NC-229 committee. The NPB has announced, in its recent Spring 2013 call for proposals, that there is an extreme need to assess the interspecies transfer of influenza virus (human to pig and vice-versa) and to assess the impact of vaccine interventions, such as vaccine use in people and pigs on the curtailment of transmission of influenza in farms and in exhibition settings and other points of concentration(8). The current outbreaks of porcine epidemic diarrhea in the US have provided a dramatic and eloquent example of how industry can timely respond, on a real time basis, to a significant infectious disease emergency. The NPB, and the AASV, backed by USDA/ APHIS have been following up the PEDV epizootics literally since the emergence of the index case and substantial emergency funds to support the most immediate needs in research have already been made available(6). These include development and validation of diagnostic testing for PEDV, understanding tissue tropism, shedding characteristics, in vitro propagation of the agent and its environmental stability. Particularly remarkable are the initiative by NPB and USDA in 2012 and again in 2013 to respond to the threat posed by the extensive dissemination through Eastern Europe of African Swine Fever Virus (ASFV), the cause of a remerging disease that threatens to expand through Western Europe, since its introduction in the Caucasus and Russiain 2007. The ASFV is considered by the US swine industry a major threat, to the point that the NPB and the competitive programs of USDA-AFRI, in a remarkable turning point, are currently funding projects based in, besides the traditional USDA labs specialized in FAD (like PIADC) local universities and other US academic laboratories associated with NC-229 in order to conduct investigations in this foreign disease(9). In the case of ASFV, the priorities established by the US swine industry include research focused towards development of tools to detect, control, and limit adverse effects from ASFV in swine. The priorities include also the development of vaccine or other type of intervention to deal with a possible outbreak of ASFV in the continental US.
The importance of the work and the consequences of failing to respond:
The US swine industry is at a crucial economic crossroads. Increased production costs and a strained economy have severely impacted many swine operations and pork producers are further hampered by infectious disease problems that increase production costs. When the viral etiology of PRRS was established by investigators in the Netherlands in 1991(11)and shortly thereafter, in the U.S. (1)research has progressed towards understanding the disease and the associated virus. The release of the first live-attenuated commercial vaccine (MLV) in June 1994 was hailed as a significant achievement and a hoped-for solution for an industry that was experiencing acute and chronic infections of PRRS virus. However, MLV have not fully met expectations; deficiencies including virus shedding, persistent infection, potential reversion to virulence and incomplete protection have been reported. Moreover, there is no method to distinguish infected from vaccinated pigs. Because of vaccine failures, many producers have sought controlled exposure or acclimation, i.e., the intentional infection of naive animals with wild-type live PRRSV either through contact with infected animals or exposure to infectious material . Thus, young pigs are exposed to farm-specific live virus in an attempt to induce immunity; however, this results in continuous spread of the virus and perhaps inadvertent spread of other diseases. There are several reasons why PRRS virus infections are difficult to control. First, mutation of the virus creates strains with unique antigenic profiles that result in poor cross-protective immunity . Second, PRRS virus elicits a rather complicated and unique immune response that subverts the immune system and results in persistently infected swine . Third, PRRSV synergizes with ubiquitous infectious agents of low virulence to produce clinically and economically significant disease syndromes, such as porcine respiratory disease complex (PRDC). Fourth, anecdotal evidence strongly suggests that the virus can efficiently move between farms, even those that utilize rigorous biosecurity and good production practices. Finally, relatively few tools, including effective vaccines and surveillance techniques, are available to producers and veterinarians for managing the disease. If ignored and left untreated, PRRS virus becomes entrenched in all phases of a production system, setting the stage for a biological "train wreck" and economic catastrophe. Even farms that survive a PRRS outbreak become re-infected despite all best efforts to protect the animals.
Porcine epidemic diarrhea virus has recently emerged and continues to spread across the country throughout many states. Initiation of research programs on PEDV was perceived by industry as an impending necessity that could not afford any delay. Herd loss may affect pork production as countless pigsmost suckling and early-weaned pigsdie from the gastrointestinal disease. Since the identification of the virus was confirmed in the United States on May 17, 2013, more than 400 cases have been reported. Cases in suckling and nursery pigs became prevalent in the middle of the summer 2013 with a high mortality rate of 30 percent to 100 percent in early-weaned pigs in naïve herds. Nursery pigs, grow/finish pigs and adult animals experience a high rate of morbidity but low mortality with the virus, any potential impact on pork supply could be expected within several months, mot ?likely towards December 2013. Typical of incipient outbreaks of an unknown disease, lack of data on pig PEDV cases makes it difficult to calculate its financial impact. How well the virus is controlled in upcoming months will be vital.
If not prevented a possible outbreak of African swine fever virus (FAD) can have a significant negative impact to producers. A recent study estimates the annual economic benefit of prevention of a FAD like ASFV just to the pork industry is worth $137million(8)
Worldwide there is great concern that the next pandemic will be caused by potential cross-species adaptation and spread of influenza viruses . Influenza viruses infect humans, swine, and avian species; they can exchange genetic sequences and produce new re-assortant viruses. Thus besides the respiratory problems caused in swine by flu viruses, swine are a potential source of new influenza viruses that can infect humans(12). This is particularly problematic given the potential for re-assortment of swine flu viruses with highly pathogenic avian influenza. Influenza is just one of numerous transboundary viral diseases of concern to the swine industry. Foot-and-mouth disease and classical swine fever virus are each major foreign animal disease threats to US producers.
Overall there is a sense of urgency and a very compelling justification for this proposed NC229 project. It presents an animal health paradigm to address future disease threats to swine and to humans. It provides new technologies to control newly emergent diseases. PRRSV was unknown just 20 years ago and PCV2b emerged in 2004 and PEDV as we speak!. Failing to solve these swine disease problems jeopardizes foreign trade in swine breeding animals, semen, and pork products; places a secure, nutritious, and wholesome food supply for the U.S. consumer at risk; and continues the downward economic spiral as farmers lose their livelihood. The new NC229 project will provide substantial opportunities to address important swine diseases based on inter-institutional cooperation at the national and international level.
The technical feasibility of the research:
Successful realization of the study objectives requires basic and applied research studies, including immunology, functional genomics, epidemiology, genetics, and molecular biology. Within this framework, NC-229 has the capacity to coordinate ideas and resources, focus on specific problems and projects, and respond immediately to new information related to virus control and elimination. It has also provided a method of dissemination through coordinated national and international meeting forums. A well documented record of such capacity of the group is represented by having attained and successfully managed two major CAP grants in PRRS during the last 10 years. This achievement attests to the expert technical know-how of the group. A remarkable spin off of the seminal funding obtained through the CAPs is represented by the continuous utilization by the group of CAP-generated results to amplify and leverage further funding through USDA NIFA competitive grants, NPB research grant program and industry funds.
The advantages of a multi-state research effort:
The NPB, NC-229 and other swine health experts have concluded that effective control of swine viruses will not rely on a single technology or solution, but on multiple strategies applied to all levels in the swine production system. While there is much expertise available from single entities, the best hope for the control and elimination of PRRSV and swineviral infections is a collaborative, multidisciplinary research program that focuses on specific aspects of the diseases. Since 2008, the NC-229 has been expanded to 14 stations (CT, GA, IA, IL, KS, MD, MO, MN, NC, NE, OH, IN, SD, and VA), 3 ARS labs (USDA-BARC, USDA-MARC, USDA-NADC), and importantly, international groups in China, Mexico and Spain.
Likely impact of successfully completing the work. The greatest impact of the successful conclusion of this research will be new paradigms for the control of PRRS and other swine viral emerging diseases. Progress toward this goal will proceed through the successful accomplishment of specific aims and milestones described later in this proposal. The creation and operation of a virtual university environment where investigators share data and ideas has been effected by the previous PRRS CAP programs. A major milestone for this NC229 renewal will be to expand this network to address the real industry problem of complex swine viral diseases. A second milestone will be risk assessment projects that will demonstrate new protocols and management techniques for the control and elimination from & Having multiple stations and researchers involved, will provide expertise in the vast array of viral diseases where knowledge in one area may translate to control in another. Therefore, not only is the NC229 consortium a multi-state multi-country multi-university group, but also a multi-pathogen related group. Communication across these collaborations will help in not only helping solve the current infectious disease problems, but also in being ready for the next emerging disease.
1. Benfield, D. A., E. Nelson, J. E. Collins, L. Harris, S. M. Goyal, D. Robison, W. T. Christianson, R. B. Morrison, D. Gorcyca, and D. Chladek. 1992. Characterization of swine infertility and respiratory syndrome (SIRS) virus (isolate ATCC VR-2332). J Vet Diagn Invest 4:127-33.
2. Meulenberg, J. J. 2000. PRRSV, the virus. Vet Res 31:11-21.
3. Mole, B. Deadly pig virus slips through US borders. Nature 499:388.
4. Mur, L., B. Martinez-Lopez, and J. M. Sanchez-Vizcaino. Risk of African swine fever introduction into the European Union through transport-associated routes: returning trucks and waste from international ships and planes. BMC Vet Res 8:149.
5. Neumann, E. J., J. B. Kliebenstein, C. D. Johnson, J. W. Mabry, E. J. Bush, A. H. Seitzinger, A. L. Green, and J. J. Zimmerman. 2005. Assessment of the economic impact of porcine reproductive and respiratory syndrome on swine production in the United States. J Am Vet Med Assoc 227:385-92.
6. NPB. 2013. PEDV Research & Resources. http://www.pork.org/Research/2641/ResearchLatestNews.aspx.
7. NPB. 2011. Pork Checkoff Study: PRRS Costs Industry $664 Million Annually
8. NPB. 2013. Spring 2013 Call for Proposals. http://www.pork.org/filelibrary/RFPs/2013/2013SpringCall.pdf.
9. PorkCheckoff. 2013. Funded research through general call http://www.pork.org/filelibrary/ResearchGrants/2013%20-%20thru%20General%20Call.pdf.
10. Tian, K., X. Yu, T. Zhao, Y. Feng, Z. Cao, C. Wang, Y. Hu, X. Chen, D. Hu, X. Tian, D. Liu, S. Zhang, X. Deng, Y. Ding, L. Yang, Y. Zhang, H. Xiao, M. Qiao, B. Wang, L. Hou, X. Wang, X. Yang, L. Kang, M. Sun, P. Jin, S. Wang, Y. Kitamura, J. Yan, and G. F. Gao. 2007. Emergence of fatal PRRSV variants: unparalleled outbreaks of atypical PRRS in China and molecular dissection of the unique hallmark. PLoS One 2:e526.
11. Wensvoort, G., C. Terpstra, J. M. Pol, E. A. ter Laak, M. Bloemraad, E. P. de Kluyver, C. Kragten, L. van Buiten, A. den Besten, F. Wagenaar, and et al. 1991. Mystery swine disease in The Netherlands: the isolation of Lelystad virus. Vet Q 13:121-30.
12. York, I., and R. O. Donis. The 2009 pandemic influenza virus: where did it come from, where is it now, and where is it going? Curr Top Microbiol Immunol 370:241-57.
Related, Current and Previous Work
Related, Current, and Previous Work:
Contributions of NC-229 investigators.
NC-229 was founded in 1999 as a vehicle to facilitate progress in Porcine Reproductive and Respiratory Syndrome (PRRS) virus research and promote collaboration and communication. NC229 originally involved the participation of 8 state universities and USDA ARS labs, increasing to 11 and 15 for the 2003/2008 renewals and to 18 for this 2013 renewal with the additional inclusion of numerous international sites. Participating institutions (names of the official NC229 representative at each location is noted): The Ohio State Univ. (R Gourapura), Univ. of Minnesota (M Murtaugh), South Dakota State Univ. (E Nelson), Univ. of Connecticut (G Risatti), Univ. of Georgia (M Tompkins), Univ. of Maryland (YJ Zhang), Univ. of Missouri (S. Schommer), Purdue Univ. (IN, R Pogranichniy), Virginia Polytechnic Institute and State University (XJ Meng), Univ. of Nebraska (F Osorio), Kansas State Univ. (R. Rowland), Iowa State Univ. (J Zimmerman), Univ. Wisconsin (T Goldberg), and Univ. of Illinois (F. Zuckermann) as well as representatives from ARS-BARC (J Lunney), ARS-NADC (K Faaberg), ARS-MARC (G Rohrer). Most recently, strong international participation has been included: China (FC Leung, Hong Kong; S Yuan, Shanghai), Mexico (J Hernandez, Sonora; R Molina, Sonora National Univ. of Mexico) and Spain (L Enjuanes, Campus Univ. Autonoma, Cantoblanco; J Dominguez, INIA). Scientists at the National Pork Board (NPB L. Becton), USDA CSREES (P Johnson), and USDA APHIS (J Srinivas, Center for Veterinary Biologics; D Pyburn and J Korslund, Veterinary Services) are active participants. Representatives from a variety of industries (animal health and vaccine and diagnostic companies) and institutions continue to participate in NC-229 activities and meetings. An annual (public) meeting, the International PRRS Symposium, has been held in December of each year immediately prior to the Conference of Research Workers in Animal Diseases (CRWAD) to discuss research findings and plan future collaborative activities. Dr. David Benfield, Ohio State Univ., a pioneer in PRRSV research, continues to serve as the Projects Administrative Advisor.
The NC-229 philosophy and approach to PRRS and respiratory disease issues is to address research problems that cannot be answered through traditional, single-investigator-initiated grants. The complexities of the problems addressed by NC-229 require a multi-state, multi-disciplinary, and multi-investigator research approach. The same philosophy and approach initially used to tackle PRRSv is now transferred to the other urgent swine emerging infections, as a real threat ( i.e. PEDV or influenza) or as an impending threat of monumental proportions (AFSV). In 2008 the National Association of State Universities and Land-Grant Colleges recognized NC-229 as the recipient of its first annual national multi-state research award, for a project that best exhibits the ideals of multi-state research, such as high standards of scientific quality, relevance to a regional priority, multi-state collaboration, and professional leadership. The Experiment Station Section Committee on Organization and Policy (ESCOP) Science and Technology committee served as the review panel. In essence, NC-229 activities are an embodiment of progress made towards understanding and eliminating PRRS and other major swine viral infections.
Examples of sustained endeavors by NC-229 participants include:
1. A history of extensive publication in the scientific literature on PRRS. A search in PubMed for papers published since 1998 to date recovered 1640 PRRS publications. In all likelihood a substantial number of these publications were written by members of NC-229 institutions. A compelling proof of the role of NC229 in producing new knowledge for the academic and professional community is represented by the sizable number of scientific reviews on the subject of PRRSV that have written by the NC-229 group within the last 5 years (2008-2013). Out of a total of 47 reviews written worldwide and covering different aspects of PRRSV, 27 of them have been written by NC-229 researchers who have participated in NC229 in the immediate past and continue as participants in this renewal (1, 5-14, 17-19, 23-25, 29, 31-33, 35-38, 40, 41, 43).
2. Success with joint multistate proposals: The NC-229 group has undoubtedly been the generating and driving force behind the successful preparation of two multimillion dollar Coordinated Agricultural Projects (CAP) : 1) PRRSV CAP1: $4.4 million USDA NRI grant #2003-05164 on the Integrated Control and Elimination of Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) in the U.S. and 2) the $4.8 million USDA NRI CAPs renewal grant #2008-55620-19132 on the Integrated strategies to control and reduce the impact of PRRS [PRRS CAP2]. Both PRRS CAP proposals dealt with complex collaborative research, education, and outreach plans via the coordinated efforts of the NC-229 multi-state consortium of PRRS researchers, academic institutions, USDA ARS labs, USDA-APHIS experts, the NPB, the American Association of Swine Veterinarians (AASV), and private industry. This is certainly a very strong proof that NC-229 has the capacity to coordinate ideas and resources, to focus on specific problems and projects.
3. Collaboration with the NPB in producer education and other special publications. The PRRS Compendium (ISBN 0-9722877-1-X), published in 2003 by the NPB, includes chapters written by 12 authors from 5 NC-229 institutions. The NC-229 coordinated the 2004 special issue of the Journal of Veterinary Immunology and Immunopathology (volume 102 #3) on PRRS immunology and Immunopathology and the 2010 special issue of Virus Research on Progress in PRRS biology and control. After the successful funding of CAP1 and CAP2, a PRRS CAP website www.prrs.org/ was created which was later has been transferred to NPB; and NC-229 participants have been assisting in the sites management since then. Interactions with professional organizations, such as the AASV, and with scientists at the 1890s and 1994 land-grant institutions are permanent and enhanced through NPB outreach activities. Moreover a significant achievement towards dissemination of knowledge originated in NC229 has been the start, since 2005, of the PRRSV symposia in conjunction with CRWAD. Those symposia became international forums attracting large and diverse audiences every year. Copies of the proceedings of each of those meetings since 2005 are attached (Appendix A).
4. Successful pursuit of competitive grants to support PRRSV and swine respiratory disease research in general. In addition to the PRRS CAP I & II grants, numerous industry grants and contracts have been awarded to NC-229 participants for pig respiratory disease research (not only for PRRSV but also including other infections such as swine influenza virus and PCV2) since 2003. Most recently several laboratories were awarded competitive funds made available by NPB to respond to the emergency posed by the appearance in the US, during the Spring 2013, of PEDV. Likewise selected laboratories located in Mid West (and other non-PIADC areas of mainland US) have received funding for ASFV. All those labs recently awarded on emerging viruses of swine are herein represented in this submission for renewal. Most importantly, it should be mentioned that during the last five years different participants of NC229 were awarded 21 competitive USDA-AFRI-NIFA grants, amounting to a total of $ 7,827,252, thus exceedingly more than duplicating the amount granted to the entire CAPII during the same period of time. Listing of the USDAAFRI NIFA awards received by the NC-229 community during the last five years is attached as Appendix B
NC229 Project Research Background:
Many of the important challenges that PRRSV still presents to the animal health community are based on the unique (rather puzzling) biology of the infection that this virus establishes in a pig. Many of the pathogenic events that occur during a swine infection by PRRSV have been characterized by NC-229 participants, either by those who work studying the host, studying the agent or also studying both. After exposure to PRRSV, a prolonged, acute productive infection takes place, characterized by viremia that may last up to 30 days post-infection or more. PRRSV begins to be (slowly) eliminated from the host when PRRSV-neutralizing antibodies and cell-mediated immunity (PRRSV-specific gamma-IFN producing cells) appear. Remarkably at odds with the kinetics of hosts response observed in the case of other swine viral infections, this incipient anti-PRRSV protective immunity begins not earlier than 4 weeks p.i. and meagerly builds up during the ensuing weeks. There is an evident inability of the host to clear PRRSV, likely explained by the different mechanisms that PRRSV employs to evade immune response. Those mechanisms may include: replication and destruction of the cell that is main viral target :, the macrophage, a major player within the immune system, ensuing cytokine storms, selective destruction of innate immunity mediators, display of decoy epitopes in structural proteins, shielding by glycans of meaningful neutralizing epitopes, and significant genetic variation, that translates into significant antigenic variation. As a consequence of these viral strategies, a persistent phase of infection follows the acute period of infection. In this late infectious phase, PRRSV persists at lower load levels in selected sites of the body, primarily lymphoid tissue. The persistence of PRRSV involves a continuous low level of viral replication but not as a true steady-state persistent infection. Indeed, the PRRSV persistent infection is eventually cleared (after several months), implying an eventual recovery of immune competence and establishment of a robust immunological memory, which is effective in preventing re-infection by homologous or closely related PRRSV strains but that can be circumvented by less cross-protective, more heterologous PRRSV strains. The most common approach to control PRRSV infections has been the use of vaccines. Different types of vaccines are in use, with the modified live strains being considered the best standard of efficacy at this time. However, the significant antigenic variation exhibited by the multiple strains of PRRSV translates in a moderate to poor efficacy in preventing infection with strains that are less related to the vaccine strain. Therefore, an effective heterologous protection to broaden the protective spectrum of vaccines is the foremost challenge to be resolved in PRRSV vaccinology research, whatever the type of vaccine or platform wed consider. Such precedence is reflected in the objective 1 of this proposal and in the research priorities established by the swine industry (NPB RFP Spring 2013)
Throughout the life of NC-229, the NC229 researchers have been tackling this and other fundamental problems posed by PRRSV to better understand the mechanisms and tools required to efficiently control PRRSV infections in the field. By way of example of current and ongoing productivity of NC-229 we can list the following outcomes reported by different laboratories within the NC-229 in their search for PRRSV solutions. These should not be envisaged as a complete list of achievements made by NC-229 in the last 5 years. The following topics, instead are individual examples taken from the most recent NC229 annual report (December 2012).
Topic 1: Need for broadening the protective coverage by PRRSV vaccines;
This important goal is being approached by several laboratories following alternative (complementary) ways. VA Tech has approached the problem of PRRSV diversity and broadening of protection X PRRSV by exploring methods of DNA shuffling of structural genes of diverging PRRSV strains, a method that at the same time seems to attenuate the virulence of the vaccine strain candidate. Ohio is investigating the enhancement of efficacy and broadening of protection through mucosal immunization approaches, combining intranasal delivery of PRRSV antigens with nanoparticle adjuvanticity .UMN, UIUC/SDSU/UNL/WIS and ISU use whole genome sequencing in pursuit of quantifying strain genetic/antigenic diversity and identifying candidate elements associated with virulence and cross-protective immunity. UMN, ISU and UNL have been pursuing the elucidation of mechanisms of induction of cross-protective antibody production as a rational basis for development of improved vaccines.
Topic 2: On which substrate to isolate and grow PRRSV?
In search for alternative cell lines to grow PRRSV for diagnostic or vaccine manufacturing purposes, UIUC has reported the development of the ZMAC macrophage cell line as a major tool for the isolation and propagation of PRRSV field strains in a swine system that is 100 % homologous to the natural target cell. While at UG (Athens) they have developed an immortalized porcine cell line (iPSC) that supports PRRS replication
Topic 3: Understanding PRRSV transmission to better control biosecurity and attain permanent maintenance of clean herds:
At UMN they have been implementing and perfecting air filtration technologies to prevent airborne introduction of PRRSV in farms, having reported significantly improved productivity of such farms after the implementation of filtration technologies .Throughout the life of this NC-229 project the cost efficiency of the system has been steadily improving.
Topic 4: Genetic resistance to PRRSV
The USDA/BARC and KSU [the PRRS Host Genetics Consortium (PHGC)]: The PHGC is aimed at dissecting the role of host genetics in resistance to PRRS and in effects on pig health and related growth effects having already identified candidate genetic markers that would facilitate marker-assisted selection.
Topic 5: Detecting PRRSV and other pathogens in a cost-efficient manner
ISU, together with SDSU have made significant advances on the use of oral fluid sample collection to assess both agents (PRRSV and flu) and their antibodies in a more practical, cost efficient manner that would eventually replace the blood sampling in large scale. UGA has also centered on oral fluids, adopting surface-enhanced Raman spectroscopy adapted to hand held devices which are oriented to pen-side detection on the patheogens ( PRRSV and influenza) in oral fluid samples.
Topic 6: PRRSV Virulence and Attenuation
UCONN and USDA/NADC have aimed at identifying PRRSV genetic determinants associated with disease caused by PRRSV will, in the long term, contribute information needed for rational engineering of PRRS live attenuated vaccines (LAV) and/or antivirals. At USDA/NADC they have reconstructed and tested in vivo, under controlled conditions, a highly pathogenic PRRSV strain that had caused the 2006-07 extensive outbreak in Asia. UMD focuses on understanding the IFN inducing/repressing phenotype of selected PRRSV strains, and its correlation with virulence and protective immunity induction.
The overall objective for this five-year NC-229 project is to reduce the impact PRRS has on producers, and to assess the feasibility and financial acceptability of PRRS area control and/or elimination for producers. To that end, we focus on the following major points, which faithfully represent the current research priorities of the US swine industry (Pork Check off NPB) : 1.1) PRRSV Immunity and Vaccinology: understanding correlates of immunity and mechanisms to broaden protection, 1.2) PRRSV Epidemiology and Surveillance: understanding virus transmission and differential testing of animals (DIVA), 1.3). Economic Impact of Interventions: determining the economic benefit of vaccination in positive herds
Develop effective and efficient approaches for detection, prevention and control of pressing viral diseases of swine of recent emergence, which includes the following: 2.1) Porcine Epidemic Diarrhea Virus, 2.2) Swine Influenza Virus, 2.3) African Swine Fever, 2.4) Emerging serotypes of swine rotaviruses
MethodsMethods: Objective 1 (Control of PRRSV) Sub objective 1.1) PRRSV Immunity and Vaccinology: understanding correlates of immunity and mechanisms to broaden protection(UMd, Ohio, UNL, VTech, UConn , UMN, UIUC, SDSU,BARC/ARS,NADC/ARS, ISU, KSU) This objective addresses PRRSV vaccinology research related to development of new generation vaccine formulations, and their evaluation in pigs based on understanding the immune correlates. Identifying the strategies by which the efficacy of modified live (PRRSV-MLV) and inactivated PRRS virus vaccine induced immune response could be improved, and in design of alternate approaches to effectively control PRRS and reduce its transmission in swine herds. (i) Identification of ideal PRRSV strains to use in new generation vaccines: Since the 1991 strain VR2332 is commonly used in the production of PRRSV-MLV vaccine, further research is warranted to evaluate other available PRRSV strains to use in design of better vaccine candidates. An ideal strategy appears to be design of genetically modified PRRSV, which is devoid of immunosuppressive properties and elicit enhanced breadth of cross-protective immunity in pigs. Methods: Methods adapted to evaluate the ideal PRRSV strains to use in future vaccine formulations include, both in vivo studies in pigs and in vitro studies using appropriate cell lines and primary cells. As the PRRSV basically has inherent immune modulating properties, generation of genetically modified virus which overcomes the immunosuppressive properties of virus appears to be advantageous. (ii) Development of stable pig cell lines for vaccine development and immunological studies: Lack of a stable permissive pig cell line to propagate PRRSV in vitro in a more natural atmosphere was overcome with the development of a porcine alveolar macrophage cell line, ZMAC. This cell line could serve as a platform to develop more successful vaccines. Methods: It is very important to develop multiple PRRSV permissive cell lines, either through transfection of virus receptive receptors on existing pig cell lines or through immortalizing the permissive pig macrophages. This is important because, PRRSV infects only a particular subset of macrophages. There are several methods to immortalize cells, such as chemicals, viruses, genetic manipulations etc. (iii) Detection of tools to rapidly measure the degree of antigenic diversity in field PRRSV isolates in relation to current vaccine strains, and identification of immunodominant PRRSV T and B cell epitopes of both structural and non-structural viral proteins. The identified epitopes may be important for the formulation of immunogens (i.e. peptide vaccines) to provide broad cross-protection against diverse PRRSV strains. Methods: To make a steady progress in development of innovative PRRSV vaccines, we need to have a cost-effective tool to constantly monitor the genetic diversity of new PRRSV field isolates, especially detected in vaccinated swine herds. Discovery of T and B cell epitopes in the entire PRRSV, predicted using computer based logarithmic approaches should be confirmed in functional studies using pig immune cells isolated from repeatedly vaccinated and/or infected adult pigs. (iv) Additional tools to understand PRRSV immunology and pathogenesis: A study identified a set of pigs with Severe Combined Immunodeficiency (SCID), which could be used as a model to identify components of immune protection in next generation vaccines. Studies have reconstructed a foreign highly pathogenic PRRSV strain under controlled conditions and used in in vitro and in vivo experiments under BSL3 safety conditions. Through this effort better understanding of the factors involved in high and low virulence infections could be determined, which are applicable in development of better vaccines. Methods: Generation of gene knockout pigs, SCID pigs, understanding the pathogenesis of different virulent and avirulent PRRSV field isolates, including the European genotype viruses. (v) To develop innovative killed PRRSV vaccine delivery system which elicits enhanced breadth of cross-protection: Mutations and reversion to virulence always exist in replicating RNA viruses like PRRSV, influenza, HIV etc. Among them PRRSV is one of the most rapidly evolving viruses; highest among RNA viruses reported so far with the evolutionary rate of 4.79.8 × 102/site/year (15). Thus, considering the widespread prevalence of PRRS virus in the US, developing an innovative inactivated PRRSV vaccine using the alternate delivery methods should be a priority. In that direction, nanotechnology based inactivated PRRSV vaccine has showed some promise. Methods: Considering the nature and pathogenesis of PRRSV in pigs, live PRRSV vaccine is not the best choice to completely control PRRS outbreaks in years to come. Thus, alternate vaccine development strategies should be encouraged and supported with optimism. Since last 10 15 years several researchers have attempted to develop novel killed PRRSV vaccines but with limited success. However, by adapting and exploring the advances made in vaccine technology to control other pathogen infections, for example nanotechnology approach; and a few other strategies already proven effective in other animal models, we may become successful one day in developing a potent killed PRRSV vaccine. But, for such studies collaborative efforts are very much needed. Our future aim should be to gradually replace PRRS-MLV and live virus infection to control field PRRS outbreaks. vi) To understand host genetic control of anti-PRRSV infection and vaccination responses. Previous work of the PRRS Host Genetics Consortium (PHGC) verified the impact of incorporating genomic and genetic tools to lessen the impact of PRRS. Working with commercial breeding programs the PHGC has identified several markers linked with clinical disease progression and resistance. A favorable "B" allele on Sus scrofa chromosome 4 (SSC4) is associated with increased weight gain and decreased virus load following controlled infection with either a 1997 or 2006 PRRSV isolate(3, 4, 34). New studies are focused on field trials for responses to natural infection and vaccination. Methods: Continued PHGC trails will investigate commercial pig responses to PRRSV infection and vaccination in controlled trials at KSU. Additional trials will compare pigs with different SSC4 alleles in field trials. Sample collection and storage will enable detailed studies of antibody, cytokine and gene expression responses in populations of commercial animals exhibiting a diversity of disease and vaccine phenotypes. Broader genotyping of each pig using the porcine 60K SNP chip will expand genome wide association studies (GWAS) to link a given phenotype with genotypes and SNP markers. Sub-objective 1.2).PRRSv Epidemiology and Surveillance: understanding virus transmission and differential testing of animals (DIVA) (UMN, ISU,NADC/ARS, UNL, KSU, SDSU) Methodology: In continuation with current projects (2008-2013), assessing the sustainability and cost-benefit of filtration as a means to reduce the risk of airborne viral spread between farms will be actively pursued. These studies will be conducted specially at UMN, which is the leading station in this sub-project. The methods to be employed for filtration analysis typically involve cohort studies, for example: a two-cohort study in which farms are classified as exposed (filtered treatment farms) or unexposed (non-filtered control farms). The study then likely involves comparison of infection rates in susceptible populations housed in non-filtered and filtered buildings/farms for periods of at least several weeks in typical clusters of farmland settings. Filtration of incoming air, in combination with standard biosecurity procedures, has been demonstrated to prevent transmission of PRRSV into susceptible herds. To quantify the impact of air filtration on reducing risk of PRRSV outbreaks, the incidence rate of new PRRSV introductions in equivalent numbers of filtered and non-filtered production units (i.e. control sow herds in a swine dense region of North America during a certain study period). Events of novel virus introduction (lateral introduction or new outbreak) are recorded by phylogenetic analysis of PRRSV ORF5 gene sequences of the new isolate. To further complete the picture of thorough biosecurity measures implementation the role of PRRSV-contaminated slurry as a means of viral spread between farms will also be evaluated. DIVA marker systems investigations: In the case of living, replicating vaccines, the methodology to follow will likely concentrate on finding ideal serologic markers that would be: 1) frankly immunodominant, 2) a peptide or part of protein that is not involved in protective immunity, 3)negligible without compromising virus viability ( in order to fulfill the requirement of being amenable to deletion, thus empowering the vaccine with negative marker potential,) and 4) to be extremely well conserved so that most if not all the animals infected with the vast majority of wt PRRSv strains can develop antibodies to these candidate serologic markers. The experiments will, in the case of live virus vaccines, be based mainly on reverse genetics methodologies. Stability of the DIVA strain developed this way should be measured in vivo and by means of virological and serological parameters. The regular N antigen ELISA will be considered the default DIVA markers in the case of all the possible sub-structural (subunit) vaccines, which most likely will be formulated with onew or more glycoproteins or other PRRSv envelope proteins. Sub-objective 1.3). Economic Impact of Interventions: determining the economic benefit of vaccination in positive (ISU/UMN/KSU) This objective addresses the fundamental need to evaluate whether specific animal health interventions are economically beneficial and, when multiple alternatives are available, which are most beneficial. (i) Development of economic models to evaluate alternative interventions. The key inputs in such models are the cost of the intervention and the expected impact on productivity and resource use (for example: feed and antimicrobials). Methods: Swine enterprise budgeting models are the preferred approach to evaluate alternative vaccine strategies. The models may be constructed to evaluate multiple interventions (scenarios). Standard market pig prices, input prices and fixed costs must be used for all scenarios so that differences in economic outcomes are due strictly to the impact of the animal health strategies. However, current values for market pig prices, input prices and fixed costs should be used as the economic outcomes are sensitive to the values entered for them. (ii) Estimate values for the key inputs in the economic models. For alternative animal health interventions, estimate the expected impact on productivity and resource use. Methods: Randomized, controlled studies may provide estimates of the productivity impacts of alternative animal health interventions that have a high level of internal validity (ie. the study is well designed and executed). However, they frequently lack external validity since the field conditions under which the animal health interventions are used may differ greatly. Therefore, large-scale cohort studies of farms using the animal health intervention (exposed) and farms not using the animal health intervention (unexposed) is the preferred approach for estimating values to be included in a swine enterprise budgeting model where the outcome will be used to provide the basis for industry-wide recommendations. As studies are done to evaluate interventions, such as filtering, production and resource use data may be collected at the same time to answer the economic question and leverage the value of these studies. Objective 2. Developing effective and efficient approaches for detection, prevention and control of pressing viral diseases of swine of recent emergence. Sub objective 2.1: Porcine epidemic diarrhea virus (ISU, KSU, UMN, OSU, SDSU, V Tech) Porcine epidemic diarrhea virus (PEDV) is not a new pathogen but a well-established enteric viral pathogen of swine, particularly in pre-weaning pigs, along with transmissible gastroenteritis virus (TGEV). Since its first recognition in England, however, PED has not been considered economically significant in Europe and has disappeared from European swine populations. This perception was changed when PEDV spread to Asia where swine producers have been having serious productivity loss due to PEDV. US swine producers share the same devastating experience with PED like Asian producers since the disease emerged in late April of 2013. Despite PEDV has been known for a long time, scientific information in literature regarding pathogenesis, immuobiology and epidemiology which can aid in effective prevention and control of PED is spare. Even available information has a limited application/utility or has been proven to be not entirely correct when applied to the US situation. It is the focus of this particular sub-objective to get better and clear understanding on these fundamental knowledge toward devising effective and efficient prevention and control of PED. 2.1.1 PEDV Diagnostics: establishing standardized laboratory methods and testing protocol for PEDV and antibodies in various sample matrices Method: 1. Effort will be made to standardize home-made PCR-based assays currently available in various diagnostic laboratories using a set of samples form pigs with known infection status and also evaluate them on unconventional sample matrices such as oral fluid and environmental samples. 2. Development of antibody assays in various platforms will be sought out for characterization of immune responses, effective surveillance and assessing the immune status of animals and populations. A DIVA concept will be explored, if applicable, for future use. 3. Production of PEDV-specific monoclonal antibodies and establishment of a repository of representative PEDV isolates will be pursued. When necessary, collaboration with commercial entities will be pursued to have licensed assays. 2.1.2 PEDV immunity and vaccinology: understanding correlates of protective immunity Method: 1. The immune ontogeny (kinetics and profile) will be studied under both experiment and field conditions. Effort will be made to identify and immune correlates of protective immunity including corresponding viral proteins. 2. Lactogenic immunity and methods to provide better lactogenic immunity, including feedback, vaccination and passive immunization, will be studied. 3. Vaccines and delivery systems conferring better mucosal immunity will be explored. 2.1.3 PEDV epidemiology and surveillance: understanding prevalence, virus transmission and molecular evolution Method: 1. As PEDV is new to US swine, it is an excellent opportunity to monitor virus evolution. Focus will be on the S gene and E gene since the current literature indicates these are related to protective immunity. Full-length sequencing will be pursued on selected viruses. 2. Factors affecting transmission of PEDV between and within herds will be characterized focusing on herd management, biosecurity measure, transportation and feed. 3. Prevalence of PEDV in US swine populations will be assessed using diagnostic data and surveys using meat juice and/or oral fluids along with assessment of economic impact of PED on US swine industry. Sub objective 2.2 Swine Influenza Virus: (UGA, IA, IL, IN, KS, MD, MN, NC, OSU, SDSU, USDA/ARS-NADC) In this objective, factors influencing virus transmission within and between swine farms will be determined to reduce economic losses caused by viral diseases. Identifying the mechanisms by which these pathogens enter, circulate and persist in swine herds is a critical step to devising methods that effectively prevent, control and/or eliminate these diseases. 2.2a. Virus Evolution and Detection. Methods: The relationships between virus diversity and evolution with the ecology, epidemiology, and virulence properties of influenza A (IAV) virus in swine will be investigated, including viruses from under-sampled pig populations in North America, at local, regional or national scales. Epidemiologic and ecologic factors such as production system type, population immunity, age of susceptibility, seasonality, and polymicrobial interactions will be assessed to determine how influenza viruses are introduced and persist on farms and how are they moved within and between production systems and globally. The genetic or genomic bases for viral fitness or virulence will be investigated. 2.2b. Control by vaccination or other interventions. Methods: The effectiveness of current and novel practices for preventing IAV infection will be evaluated, identifying immune parameters that are correlates of heterologous protection with traditional and/or new vaccine platforms or evaluating new vaccine strategies such as those targeting different age groups or seasonal whole-herd vaccinations versus vaccinating breeding animals on production schedules. The extent that genetic diversity impacts antigenic diversity and suboptimal immunity contributes to evolution of influenza viruses in swine will be evaluated. Alternative interventions to prevent new introductions to swine herds will be investigated. 2.2c. Impact of influenza A at the human-animal interface. Methods: The impact of human to swine, swine to human or other risk of interspecies transmission of IAV to swine will be assessed to define the ecological and genetic determinants for human seasonal viruses to periodically transmit to swine, the adaptations required for sustained transmission of human or avian viruses in swine, if humans can be asymptomatic carriers of swine influenza and contribute to the movement of swine influenza viruses, the risk factors for zoonotic transmission of influenza from swine to humans, and the genetic determinants or adaptations required for sustained transmission of swine viruses in humans. Objective 2.3 Improved Disease Control for African Swine Fever (ASF): Vaccine Design and Development - (UIUC, UNL, ISU, SD, KS, CT, TX, WI, AZ, Plum Island Animal Disease Center, ARS, USDA and National Research Institute for Veterinary Virology and Microbiology, Pokrov, Russian Federation). ASF is arguably the most significant emerging disease threat for the swine industry worldwide. Devastating ASF disease outbreaks and the continuing disease epidemic in the Caucasus region and Russia (2007 to date) highlight the significance of the threat. There is no vaccine for ASF available; however, it is clear that vaccination is possible since protection against homologous re-infection has been definitively demonstrated. Vaccine progress is hindered by the fact that the extent of ASFV strain variation and variability and the viral antigens responsible for protective immunity remain unknown The overall goal of work outlined in this objective is to provide critical foundational information on ASFV strain variation and identify viral protein(s) associated with protective immunity, thus enabling rationale ASFV vaccine design/development. The availability of effective ASF vaccines will significantly reduce the disease risk for US agriculture and food systems. Objective 2.3a . Define ASFV strain diversity and identify genetic signature(s) for ASFV serologic group specificity/cross protective immunity - Knowledge of ASFV strain diversity and the breadth of strain variation in nature, and notably diversity of relevant protective antigens, will enable development of rapid genotyping methods capable of discriminating among viruses of specific serotype and predicting efficacy of a given vaccine for an outbreak field strain. Better understanding of diversity among protective antigens will also facilitate design and development of more efficacious immunogens. Methods: Comparative ASFV genomic analysis will be used to identify genetic signatures of viral proteins that correlate with the serogroup/cross protective immunity and signatures modeled to provide power in prediction of biological serotype specificity based on sequence information alone. Partition analysis will be used to statistically associate genotypic signatures with phenotype. Hidden Markov models will be used to generate serotype-specific sequence profile models for grouping other ASF virus isolates of unknown serotype/cross protection group. Available collections of ASFV isolates will be evaluated to better define the extent of virus variation in nature. 2.3 b. Identify ASF viral protein(s) responsible for protective immunity Identification and prioritization of ASFV protective antigens will permit development of subunit-vectored vaccines and rationally engineered live-attenuated vaccine candidates that will DIVA (Differentiate Infected from Vaccinated Animal) compatible and suitable for use under emergency conditions in nonendemic countries such as the United States and Europe. Methods: Putative ASFV protective antigens (PA) will be identified using analysis described in 2.3a above and evaluated using ASFV chimeric and/or gene-deleted viruses or other gene delivery vectors in vaccination/challenge experiments in pigs. Host responses correlated with protection will be identified. PAs will be prioritized and the most promising candidates evaluated further as vectored subunit antigens in vaccination/challenge experiments in pigs.
Measurement of Progress and Results
- " Data published in peer-reviewed scientific literature, as well as data and interpretations published in industry newsletters and other publications targeted to the swine industry and allied providers. Given the significance of the focused objectives adopted by NC-229 in this proposal we anticipate that the rate of data produced will be consistent with or even higher than the productivity demonstrated by NC229 throughout the last 15 years.
- " Continue the number and quality presentations at meetings, workshops, and symposia attended by swine veterinarians and members of the swine industry. These include the annual International/North American PRRS Symposium, the Annual NC229 meeting and CRWAD swine diseases and viral pathogenesis sessions, as well as meetings of the American Association of Swine Veterinarians, the International Pig Veterinary Society, the Iowa State Univ. Swine Health Conference, and the Allen D. Leman Swine Conference.
- " Maintain cross-talk and increase partnership with NC-229 equivalent groups in other countries and continents ( i.e COST Action network EuropRRS.net, Simposio Internacional PRRS Mexico 2012-2013, etc)
- " Continue expansion of standard methods, protocols, and reagents for serological, immunological, and virological assessments of virus-host swine interactions.
- " Continue educational and training manuals, CDs, pamphlets and literature related to biosecurity, biosecurity implementation and biosecurity monitoring.
Outcomes or Projected Impacts
- " Production of value-added swine and pork products through the diagnosis and control of PRRSV and emerging viral disease in breeding herds and genetic stocks
- " Increased global competitiveness of the U.S. swine industry by eliminating the cost of PRRS and by producing PRRS-free pigs.
- " Lead the worldwide research community towards the concept of a feasible immunization strategy against ASFV targeted to endemic areas of the world.
- " Prevent the introduction of ASFV in North America. Develop and increase preparedness.
- " Improved food safety by elimination of disease agents most impactful on health in swine, including PEDV and influenza.
- Outcome/impact 6:Promotion of greater harmony between agriculture and the environment by the development of more efficient and sustainable swine production practices through elimination of the most significant health hazard to swine.
Milestones(2015): see appendix C
(2016): see appendix C
(2017): see appendix C
(2018): see appendix C
(2019): see appendix C
Projected ParticipationView Appendix E: Participation
Outreach Plan: The NC229 Committee members will develop educational outreach tools for disseminating information through established outreach and extension networks to producers, veterinarians, educators, and researchers. These will be coordinated and directed through the NPB. As specific knowledge is acquired on topics of PRRS and other swine viral diseases elimination, diagnosis and prevention, educational materials and operation manuals will be prepared and distributed via print and electronic media under the direction and coordination of the NPB. Examples of such actions are the ongoing working groups organized by NPB to revise and update PRRSV research goals, that we anticipate will originate novel, publishable, comprehensive reviews of the major topics of PRRSV.
Scientific communication will be managed by the NC-229 committee to assure full reporting of research findings in peer-reviewed scientific literature, abstracts and proceedings of relevant meetings and symposia, book chapters, and review articles. Timely communication will occur through the annual NC229 meeting and affiliated international/national symposia, particularly at the International/North American PRRS Symposia and CRWAD viral pathogenesis sessions. This renewal includes international participants in China, Mexico, Spain and Russia. This expansion will help to expand opportunities for material interchanges, research planning a sharing of resources, and outreach.
Lists, descriptions, and sources of control standards, assay protocols, planned experiments, critical reagents, clones, and so forth will be permanently available for PRRS virus researchers on an NPB server. A host response database has already been developed by the PRRS Host Genetics Consortium and derived thanks to CAP2 funding to store and interrogate data on host genetics and host phenotypic responses to infection or vaccination.
Organization and Governance:
The program will be directed by the chair of NC-229 working with an executive committee comprising the chair, the past chair, and the secretary. Elections for chair and secretary are held every two years. The validity of NC-229 research objectives during the lifespan of this project will be gagged by input received from the National Pork Board ( their swine health committee or other ad hoc groups composed by NPB) and the American Association of Swine Veterinarians AASV at least once a year at the time of their annual meetings.
1. Althouse, G. C., and K. Rossow. The potential risk of infectious disease dissemination via artificial insemination in swine. Reprod Domest Anim 46 Suppl 2:64-7.
2. Benfield, D. A., E. Nelson, J. E. Collins, L. Harris, S. M. Goyal, D. Robison, W. T. Christianson, R. B. Morrison, D. Gorcyca, and D. Chladek. 1992. Characterization of swine infertility and respiratory syndrome (SIRS) virus (isolate ATCC VR-2332). J Vet Diagn Invest 4:127-33.
3. Boddicker, N., E. H. Waide, R. R. Rowland, J. K. Lunney, D. J. Garrick, J. M. Reecy, and J. C. Dekkers. Evidence for a major QTL associated with host response to porcine reproductive and respiratory syndrome virus challenge. J Anim Sci 90:1733-46.
4. Boddicker, N. J., D. J. Garrick, R. R. Rowland, J. K. Lunney, J. M. Reecy, and J. C. Dekkers. Validation and further characterization of a major quantitative trait locus associated with host response to experimental infection with porcine reproductive and respiratory syndrome virus. Anim Genet.
5. Cecere, T. E., S. M. Todd, and T. Leroith. Regulatory T cells in arterivirus and coronavirus infections: do they protect against disease or enhance it? Viruses 4:833-46.
6. Chand, R. J., B. R. Trible, and R. R. Rowland. Pathogenesis of porcine reproductive and respiratory syndrome virus. Curr Opin Virol 2:256-63.
7. Christopher-Hennings, J., E. A. Nelson, G. C. Althouse, and J. Lunney. 2008. Comparative antiviral and proviral factors in semen and vaccines for preventing viral dissemination from the male reproductive tract and semen. Anim Health Res Rev 9:59-69.
8. Corzo, C. A., E. Mondaca, S. Wayne, M. Torremorell, S. Dee, P. Davies, and R. B. Morrison. Control and elimination of porcine reproductive and respiratory syndrome virus. Virus Res 154:185-92.
9. Cruz, J. L., S. Zuniga, M. Becares, I. Sola, J. E. Ceriani, S. Juanola, J. Plana, and L. Enjuanes. Vectored vaccines to protect against PRRSV. Virus Res 154:150-60.
10. Dee, S., S. Otake, and J. Deen. Use of a production region model to assess the efficacy of various air filtration systems for preventing airborne transmission of porcine reproductive and respiratory syndrome virus and Mycoplasma hyopneumoniae: results from a 2-year study. Virus Res 154:177-84.
11. Desrosiers, R. Transmission of swine pathogens: different means, different needs. Anim Health Res Rev 12:1-13.
12. Faaberg, K. S., M. E. Kehrli, Jr., K. M. Lager, B. Guo, and J. Han. In vivo growth of porcine reproductive and respiratory syndrome virus engineered nsp2 deletion mutants. Virus Res 154:77-85.
13. Fang, Y., and E. J. Snijder. The PRRSV replicase: exploring the multifunctionality of an intriguing set of nonstructural proteins. Virus Res 154:61-76.
14. Gillespie, J., T. Opriessnig, X. J. Meng, K. Pelzer, and V. Buechner-Maxwell. 2009. Porcine circovirus type 2 and porcine circovirus-associated disease. J Vet Intern Med 23:1151-63.
15. Hanada, K., Y. Suzuki, T. Nakane, O. Hirose, and T. Gojobori. 2005. The origin and evolution of porcine reproductive and respiratory syndrome viruses. Mol Biol Evol 22:1024-31.
16. Holtkamp, D. J., J. B. Kliebenstein, E. J. Neumann, J. J. Zimmerman, H. Rotto, T. K. Yoder, C. Wang, P. Yeske, C. Mowrer, and C. Haley. 2013. Assessment of the economic impact of porcine reproductive and respiratory syndrome virus on United States pork producers. J. Swine Health Prod. 21:72-84.
17. Huang, Y. W., and X. J. Meng. Novel strategies and approaches to develop the next generation of vaccines against porcine reproductive and respiratory syndrome virus (PRRSV). Virus Res 154:141-9.
18. Kittawornrat, A., J. Prickett, W. Chittick, C. Wang, M. Engle, J. Johnson, D. Patnayak, T. Schwartz, D. Whitney, C. Olsen, K. Schwartz, and J. Zimmerman. Porcine reproductive and respiratory syndrome virus (PRRSV) in serum and oral fluid samples from individual boars: will oral fluid replace serum for PRRSV surveillance? Virus Res 154:170-6.
19. Lunney, J. K., and H. Chen. Genetic control of host resistance to porcine reproductive and respiratory syndrome virus (PRRSV) infection. Virus Res 154:161-9.
20. Meulenberg, J. J. 2000. PRRSV, the virus. Vet Res 31:11-21.
21. Mole, B. Deadly pig virus slips through US borders. Nature 499:388.
22. Mur, L., B. Martinez-Lopez, and J. M. Sanchez-Vizcaino. Risk of African swine fever introduction into the European Union through transport-associated routes: returning trucks and waste from international ships and planes. BMC Vet Res 8:149.
23. Murtaugh, M. P., and M. Genzow. Immunological solutions for treatment and prevention of porcine reproductive and respiratory syndrome (PRRS). Vaccine 29:8192-204.
24. Murtaugh, M. P., T. Stadejek, J. E. Abrahante, T. T. Lam, and F. C. Leung. The ever-expanding diversity of porcine reproductive and respiratory syndrome virus. Virus Res 154:18-30.
25. Music, N., and C. A. Gagnon. The role of porcine reproductive and respiratory syndrome (PRRS) virus structural and non-structural proteins in virus pathogenesis. Anim Health Res Rev 11:135-63.
26. Neumann, E. J., J. B. Kliebenstein, C. D. Johnson, J. W. Mabry, E. J. Bush, A. H. Seitzinger, A. L. Green, and J. J. Zimmerman. 2005. Assessment of the economic impact of porcine reproductive and respiratory syndrome on swine production in the United States. J Am Vet Med Assoc 227:385-92.
27. NPB. 2013. PEDV Research & Resources. http://www.pork.org/Research/2641/ResearchLatestNews.aspx.
28. NPB. 2013. Spring 2013 Call for Proposals. http://www.pork.org/filelibrary/RFPs/2013/2013SpringCall.pdf.
29. Opriessnig, T., L. G. Gimenez-Lirola, and P. G. Halbur. Polymicrobial respiratory disease in pigs. Anim Health Res Rev 12:133-48.
30. PorkCheckoff. 2013. Funded research through general call http://www.pork.org/filelibrary/ResearchGrants/2013%20-%20thru%20General%20Call.pdf.
31. Prickett, J. R., and J. J. Zimmerman. The development of oral fluid-based diagnostics and applications in veterinary medicine. Anim Health Res Rev 11:207-16.
32. Renukaradhya, G. J., V. Dwivedi, C. Manickam, B. Binjawadagi, and D. Benfield. Mucosal vaccines to prevent porcine reproductive and respiratory syndrome: a new perspective. Anim Health Res Rev 13:21-37.
33. Rowland, R. R. The interaction between PRRSV and the late gestation pig fetus. Virus Res 154:114-22.
34. Rowland, R. R., J. Lunney, and J. Dekkers. Control of porcine reproductive and respiratory syndrome (PRRS) through genetic improvements in disease resistance and tolerance. Front Genet 3:260.
35. Sang, Y., R. R. Rowland, and F. Blecha. Interaction between innate immunity and porcine reproductive and respiratory syndrome virus. Anim Health Res Rev 12:149-67.
36. Shi, M., T. T. Lam, C. C. Hon, R. K. Hui, K. S. Faaberg, T. Wennblom, M. P. Murtaugh, T. Stadejek, and F. C. Leung. Molecular epidemiology of PRRSV: a phylogenetic perspective. Virus Res 154:7-17.
37. Sun, Y., M. Han, C. Kim, J. G. Calvert, and D. Yoo. Interplay between interferon-mediated innate immunity and porcine reproductive and respiratory syndrome virus. Viruses 4:424-46.
38. Sun, Z., C. Liu, F. Tan, F. Gao, P. Liu, A. Qin, and S. Yuan. Identification of dispensable nucleotide sequence in 3' untranslated region of porcine reproductive and respiratory syndrome virus. Virus Res 154:38-47.
39. Tian, K., X. Yu, T. Zhao, Y. Feng, Z. Cao, C. Wang, Y. Hu, X. Chen, D. Hu, X. Tian, D. Liu, S. Zhang, X. Deng, Y. Ding, L. Yang, Y. Zhang, H. Xiao, M. Qiao, B. Wang, L. Hou, X. Wang, X. Yang, L. Kang, M. Sun, P. Jin, S. Wang, Y. Kitamura, J. Yan, and G. F. Gao. 2007. Emergence of fatal PRRSV variants: unparalleled outbreaks of atypical PRRS in China and molecular dissection of the unique hallmark. PLoS One 2:e526.
40. Wang, X., and J. Christopher-Hennings. Post-transcriptional control of type I interferon induction by porcine reproductive and respiratory syndrome virus in its natural host cells. Viruses 4:725-33.
41. Welch, S. K., and J. G. Calvert. A brief review of CD163 and its role in PRRSV infection. Virus Res 154:98-103.
42. Wensvoort, G., C. Terpstra, J. M. Pol, E. A. ter Laak, M. Bloemraad, E. P. de Kluyver, C. Kragten, L. van Buiten, A. den Besten, F. Wagenaar, and et al. 1991. Mystery swine disease in The Netherlands: the isolation of Lelystad virus. Vet Q 13:121-30.
43. Yoo, D., C. Song, Y. Sun, Y. Du, O. Kim, and H. C. Liu. Modulation of host cell responses and evasion strategies for porcine reproductive and respiratory syndrome virus. Virus Res 154:48-60.
44. York, I., and R. O. Donis. The 2009 pandemic influenza virus: where did it come from, where is it now, and where is it going? Curr Top Microbiol Immunol 370:241-57.