Although this paper was written before the current new-variant H1N1 epidemic it provides an excellent overview of the current swine influenza surveillance program. It was originally presented at the 40th Annual Meeting of the AASV in March 2009 at Dallas in Texas.

In July 2008, the Centers for Disease Control and Prevention’s (CDC) National Center for Immunization and Respiratory Diseases (NCIRD) Influenza Division (ID) and the US Department of Agriculture’s (USDA) Animal and Plant Health Inspection Service (APHIS) Veterinary Services (VS), specifically the National Veterinary Services Laboratories (NVSL), entered into an inter-agency agreement regarding swine influenza virus (SIV) surveillance. A parallel agreement was reached between CDC and USDA-Agricultural Research Service (ARS) for related research efforts on isolates derived from the APHIS program.

Brief Overview of Current SIV Situation in Swine

The SIV paradigm changed dramatically in the late 1990s in the United States with the emergence of an H3N2 sub-type in several swine populations. This was a triple reassortant virus, containing swine, avian and human influenza A virus genes. Since 2000, multiple reassortant events have occurred between this new virus and the “old” or classical SIV (the cH1N1 subtype) resulting in the production of multiple strains of SIVs.^1,2,3 Moreover, additional human H1 and H3 genes have been introduced into swine viruses, contributing to a state of continual change in the SIV genome. Based on experimental studies, some of these new viruses can be more pathogenic than their predecessors^4,5.

Reassortant SIV is of increasing concern to animal health due to its proclivity for exchange of genetic material with influenza viruses of other species, particularly human and avian hosts and its ability to mutate rapidly. The swine industry has identified SIV-related respiratory disease as a serious health and economic problem to the US swine industry⁶. The large number of sub-types and genotypes of SIV circulating among US herds has complicated management efforts to control SIV outbreaks and pig losses to SIV have increased^7,8.

The epidemiology of SIV is complex. Transmission dynamics are poorly understood. Swine vaccines (including autogenous products) are often ineffective or only transiently effective as virus genomic drift and shift occurs. Local and national data on SIV and SIV strain prevalence and distribution are lacking, hindering progress toward better understanding the disease and its control.

Accurate SIV diagnosis is increasingly complicated and expensive. USDA often lacks access to the most current viral genetic material for reagent preparation and analysis due to lack of a coordinated laboratory sharing process. This has compromised standardised and accurate SIV diagnosis due to the unavailability of updated reagents at diagnostic labs^9,3.

The National Animal Disease Center (NADC) is a section of the ARS, housed at Ames, Iowa. The centre conducts SIV research but currently, it lacks staffing and funding to perform necessary advanced SIV characterisation and inoculation studies.

Reassortant SIV with shared genetics from humans and swine is also of increasing zoonotic concern. Although interspecies transmission of influenza virus is not common, there is considerable evidence establishing the bidirectional exchange of influenza viruses between pigs and humans^10,11. During a 1976 outbreak of swine H1N1 influenza in over 200 humans, the virus was found to be antigenically and genetically identical to a recent swine influenza outbreak subtype¹². Currently, human-swine-avian reassortant viruses of subtypes H3N2, H1N2 and H1N1 influenza viruses are circulating in pigs throughout the United States³. Recent findings have shown that new or novel reassortant influenza viruses have been transmitted between humans and pigs^10,13. Zoonotic SIV infection risks need to be better understood and their incidence better documented.

Historically, reports from North America of SIV sub-types being isolated from humans with influenza-like illness have generally been limited to one or two cases per year. From December 2005 to January 2008, nine human cases of swine influenza infection have been identified in the United States. Seven of these cases reported exposure to pigs in commercial settings, live animal markets or at fairs.

In most cases with known swine exposure, pigs were reported to have displayed clinical signs of respiratory illness. Unfortunately, follow-up investigations were either delayed or limited so the actual source of some of the human infections was not clear¹³.

Triple reassortant swine influenza A (H1N1) infections and disease in humans were identified in Iowa, Illinois and Ohio in 2007¹³. Concurrent swine and human infections with an identical SIV isolate were reported in the Ohio case.¹⁴. Further, a published report postulated that US swine workers and their non-swine-exposed spouses had increased risk of SIV infection compared to people without swine exposure, based on increased percentages of SIV titres in these cohorts¹⁵.

Collectively, these incidents, along with previously published clinical reports describing human SIV infection, have raised concerns for the zoonotic threat of SIV to human health. The recent reported increase in swine influenza virus infections in humans may reflect an increased ability of SIV triple reassortants to infect humans, or may simply reflect increased awareness, reporting, and diagnostic capabilities for novel human influenza infections. SIV potentially has adverse economic implications related to perceived domestic product safety and foreign trade issues for the swine industry. Emergence of a severe SIV strain could lead to large production losses and pressure for a regulatory animal disease emergency response to address the issue.

Currently, veterinarians are sending samples from swine with clinical signs that are consistent with SIV to university diagnostic laboratories, including the National Institutes of Health (NIH) Centers of Excellence, NVSL, and USDA-ARS-NADC on a limited basis and at the request of individual veterinarians for diagnostic purposes. However, no routine standardised SIV surveillance is in place.

Surveillance Need Identified

In late 2007, USDA-APHIS-VS began seeking funds to initiate national SIV surveillance in the fiscal year 2010 budget in response to the more dynamic SIV paradigm. Initial goals of national SIV surveillance are to understand better the epidemiology and ecology of SIV in swine in the United States. This includes establishing strain incidence and distribution of SIV in the US and identifying novel isolates that may cause more severe clinical illness in swine. A novel isolate is defined as an isolate of a sub-type not currently circulating widely among US pig herds. This includes those of avian origin. Additional information on the risk and role of human influenza in pigs was also determined to be a potential factor in the design and implementation of surveillance programs to further reduce the risk to swine herds.

Two early objectives were developed to better understand the epidemiology and ecology of SIV in swine in the United States:

1. Routinely detect changes in the SIV genome of isolates from cases defined by increased swine herd mortality and/or associated with suspect human exposure-related cases of influenza-like illness, described in case submissions to National Animal Health Laboratory Network (NAHLN)-associated diagnostic laboratories from producers through swine veterinarians.
2. Collect, analyse and disseminate accessible geographical and temporal epidemiological data related to SIV-positive cases and the more virulent genomic sequences of interest to animal health officials.

Collaborative Project Opportunity with CDC

In April 2008, CDC extended an SIV surveillance-related funding offer to USDA for virus characterisation of SIV isolates and improved understanding of the relevance of cross-species swine-human SIV infections. USDA saw this proposal as an opportunity to fund some SIV surveillance immediately while recognising the benefits for both animal and human health. USDA entered into two inter-agency agreements with CDC’s Influenza Division, which provide USDA-VS and the USDA-ARS-NADC with a total of $1.5 million in funding for SIV surveillance. This pilot project is of limited duration and will serve as a precursor to a possible USDA-funded SIV surveillance plan.

CDC’s interest in SIV is primarily driven by its responsibility for human influenza pandemic preparedness, a high priority for the US government. In June 2007, the Council for State and Territorial Epidemiologists (CSTE) reporting requirements were amended to make novel human influenza A infection (including all human SIV infections) a nationally notifiable condition for physicians. Since pigs serve as a source of novel influenza A viruses for human infection, it is important to understand influenza virus circulation in pigs and to assess the risk that these swine viruses pose to humans. In certain circumstances where human illness from swine influenza has occurred, SIV isolates have been shared with CDC by animal health officials. However, intellectual property constraints and issues of limited coordination and communication among multiple local, state, federal and non-governmental entities have resulted in missed opportunities to better understand the epidemiology and ecology of SIV in pigs and people.

A main goal of human pandemic preparedness is rapid identification of novel influenza A virus infections in humans to generate an early response. Most instances of human infection with animal influenza viruses do not result in human-to-human transmission but each case should be fully investigated to ensure that such viruses are not spreading among humans. An effective response must also limit further human exposure to infected animals, if identified as a source of infection.

CDC lacks current data on SIV strain incidence in swine populations and lacks access to SIV isolates for evaluation. Constant updating of diagnostic reagents for public health laboratories is key to early identification of novel influenza A viruses in people. Finally, early detection of dangerous human SIV isolates would speed development of potential zoonotic swine influenza vaccine candidates for humans.

Pilot SIV Surveillance Plan

VS-NVSL, National Surveillance Unit and VS swine programme staff, collaborating with ARS-NADC and CDC, developed an abbreviated surveillance plan, statement of work and budget for the collaborative project. The pilot plan specifies permission-negotiated sharing of SIV information and isolates by all participants.

The pilot surveillance project is intended to be mutually beneficial to the swine industry, USDA, and the CDC. Table 1 lists the project’s anticipated outcomes. Its overall objectives are to:

1. Rapidly detect changes in swine influenza virus to better understand the impact of SIV changes on swine health.
2. Provide diagnostic, epidemiological, and experimental data regarding SIV infection to swine stakeholders to assist in development of new diagnostic reagents for swine, provide information for vaccine updates, and improve biosecurity practices to minimize transmission
3. Cooperate with CDC in identification of SIV viruses that may pose a threat to human health, improve diagnostic reagents for human influenza diagnosis, develop improved human biosecurity practices to minimise transmission and provide swine influenza viruses to CDC for the development of diagnostic reagents for human public health laboratories. In addition, human vaccine candidates may be developed based on pathogenicity and transmission studies in non-pig animal models conducted at CDC. Such diagnostic reagents and vaccine candidates for human health are provided by CDC at no cost to domestic and international public health laboratories as part of CDC’s role as a World Health Organization (WHO) collaborating centre.

VS’s primary overriding goal for this collaboration is to initiate an SIV surveillance pilot project, which may serve as a precursor to a potential USDA-funded swine surveillance programme. Through the pilot project, VS and its stakeholders have the opportunity to refine case definitions, establish and test sampling streams, and solve data collection issues that can facilitate epidemiological analysis of SIV in US swine populations.

Veterinary Services Responsibilities

In the project, USDA-APHIS-VS is tasked with:

1. Developing the pilot SIV surveillance project in coordination with AASV, NPB and CDC
   Industry and swine practitioner involvement and cooperation is essential for the success of the surveillance effort.
2. Writing case definitions
   Cases for submission initially include those in which disease is unusually severe in pigs, cases in which the influenza viruses are novel to pigs (non-H1 or H3), or cases in which human illness in association with influenza-related illness in swine has been reported. AASV, NPB, CDC, and VS are coordinating further development of case definitions.
3. Providing appropriate education and communication to swine veterinarians, selected industry representatives, diagnostic labs and state and federal veterinarians regarding SIV surveillance, case definitions, sample submission, and required epidemiological information.
4. Standardising and coordinating the collection, storage and analyses of swine case samples that meet case definitions and the associated epidemiological and genomic data
   This includes the collection and sharing of epidemiological information, tissue samples, and virus isolates between veterinary diagnostic labs, NAHLN, NVSL, NADC and CDC.
5. Developing and maintaining a project database
   The database will document and manage all SIV case-defined data, including negative as well as positive test results. The database will document isolates that may indicate a possible genetic drift or shift toward a more virulent isolate in swine or that may have implications for human health.
6. Analysing the epidemiological data and providing timely stakeholder-specific summary reports
   Quarterly progress reports and end-of-year progress reports will be provided to CDC as the funding agent.

VS and CDC will jointly develop a framework for improved cooperation and communication between federal, state, and local animal and public health officials as part of the agreement. Both CDC and VS agree to timely notification of appropriate public health and animal health officials regarding suspected human SIV infections related to a swine interface event. The framework will include detailed guidance on notification and delineate investigation roles and responsibilities.

CDC will receive epidemiological and genomic swine surveillance data, as well as a negotiated number of virus isolates and/or products from defined cases. Isolates of interest to CDC are representative of SIV circulating in US swine, SIV outbreaks among pigs in which there are suspect or confirmed human SIV cases related to a human-swine interface event, and unusual or severe outbreaks of SIV among pigs, especially those involving any novel influenza A isolates. Both VS and CDC will also work with participating NAHLN labs to minimize any intellectual property rights issues for the SIV isolates, with the goal that isolates be provided without material transfer agreements. Isolates would be made available to CDC for purposes related to human vaccine and diagnostic reagent development and surveillance.

CDC Influenza Division Responsibilities

Beyond providing funding for the project in late 2008, CDC agrees to report to APHIS-VS any suspect or confirmed human influenza cases reported through public health channels that are potentially associated with swine exposure.

CDC will also be jointly responsible for developing the notification framework for improved cooperation and communication between federal, state, and local animal and public health officials, as previously described. Under the agreement, CDC will:

• Share data and isolates without restriction. CDC staff will provide updates on new variants of human seasonal influenza A viruses as they emerge, and will send viruses, inactivated antigens and antiserum upon request to NVSL.
• Transparently outline CDC’s activities associated with receipt of SIV information and isolates. Such activities may include the following, particularly if there is an increased risk to human health:

- Notify APHIS-VS if SIV isolates are shared with WHO collaborating centres based on risk to human health
- Offer co-authorship to USDA-NADC and APHIS-VS staff if any manuscripts are prepared using SIV information derived from virus samples provided by USDA, to the extent that such co-authorship is consistent with prevailing academic practices and in accordance with agency authorship policies
- Conduct risk assessment for human health including assessment of receptor binding specificity, pathogenesis and transmission potential in humans and antigenic properties related to human vaccine production
- Develop primers/reagents that can be used in diagnostic assays and test kits
- Test the performance of the primers and reagents using live virus
- Develop test kits for use with human biological samples and virus isolates
- Distribute test kits and the virus within the WHO Global Influenza Surveillance Network to human influenza vaccine manufacturers if human disease appears to be occurring at levels that would warrant vaccine production
- Store the virus in a “library” for potential future use by CDC and others for human health-related purposes, including the development of a commercial human vaccine.

Stakeholder Benefits

This collaborative project will provide a number of benefits to APHIS-VS, NADC, CDC and other agencies and industry stakeholders by facilitating cooperation among those directly affected by the surveillance programme.

The swine industry will benefit from improved SIV vaccine information. Vaccine manufacturers and APHIS Center for Veterinary Biologics (CVB) will receive timely SIV strain and epidemiological information to assist in analysing vaccine candidates for likely homology with prevalent SIV strains. Scientific data to enable necessary vaccine research, development and technology transfer will be made available through published USDA reports.

Improved standardised SIV diagnostic capabilities will be available to the industry through a coordinated veterinary laboratory and research infrastructure. Under the surveillance plan, accredited veterinarians will be paid for case-compatible submissions leading to successful SIV diagnosis. The agreement will also fund laboratory work for partial or full antigen typing, including genomic sequencing information and selected animal inoculation studies from cases of special interest. This information will be shared with the submitting veterinarians and their clients, with wider sharing of less specific case information.

Another potential benefit is an improved understanding of the epidemiology and ecology of SIV in swine and people, and more information on the potential impact of SIV exposure on humans and swine in occupational and exhibition settings. Appropriate occupational protection guidance will be refined, based on improved understanding of infection risk in humans. The project will increase public awareness of the industry’s proactive response to a potential public health issue at the human-animal interface.

Swine vaccine and reagent companies, APHIS-CVB, and the entire industry will benefit from improved diagnostic reagents for use at veterinary diagnostic labs. In addition, a national public SIV data set will contain full genomic sequencing information from cases of special interest, tied to epidemiological data to allow a better understanding of ecology and genetic diversity of SIV infections. SIV sequence data will also be made available to the public through a public genetic database (for example, GenBank®)¹⁶ and/or alternate SIV genomic databases.

Federal and state regulatory veterinarians will gain an improved understanding of the epidemiology and ecology of SIV from national data. The programme will develop agency partnerships to address known swine health and potential public health issues at the human-animal interface. Also, the pilot project will identify issues to consider for continued SIV surveillance activities and may provide useful experience in further development of an integrated swine health programmes management and IT structure.

NVSL will benefit from widespread selection of isolates for improved preparation of reference products (antigen and sera). Also, the laboratories will gain full genomic sequencing information from cases of special interest (performed by NADC under a separate interagency agreement). Improved understanding of the epidemiology, ecology and genetics of SIV from national public data will allow improved diagnostic capabilities for animal laboratories. Benefits for NAHLN laboratories include payment for polymerase chain reaction (PCR) and viral isolation (VI) efforts on case-compatible samples, standardised and improved diagnostic tools, full genomic sequencing information from cases of special interest and national data that may improve understanding of the epidemiology, ecology, and genetics of SIV.

Under the collaboration, NADC will benefit from enhanced acquisition of novel SIV viruses of special interest for study. NADC will also receive funding for research and analysis of novel SIV isolates. The resulting national data from this project will improve understanding of SIV epidemiology, ecology, and genetics. Scientific data will enable necessary vaccine research and technology transfer.

The project will assist CDC in better defining the risk and impact of SIV exposure at the human-animal interface, generate human diagnostic reagents for emerging SIV viruses and develop possible human influenza vaccine strategies. CDC will also benefit by developing and enhancing collaborative relationships with industry and animal health regulatory agencies at all levels. These strengthened relationships will improve pandemic preparedness in the United States and improve knowledge of the epidemiology, ecology and genetics of SIV in swine via a national public data set.

Conclusion

Since 1998, SIV has evolved into a much more complex and challenging swine disease due to the instability of the viral genome. This instability continues to frustrate both diagnosis and generation of consistently effective immunity in swine herds. In addition, evidence suggests that current SIV genetic variability may increase the zoonotic potential for this pathogen.

These factors have led to development of a relatively novel surveillance effort between animal and public health regulatory agencies relying upon swine industry cooperation. All stakeholders will potentially derive benefits through this cooperative effort to better document the changes occurring in this long-time swine pathogen. The SIV surveillance plan is still in the early stages of implementation at the time of manuscript submission. Further plan revisions and data to date will be provided in March 2009 at the AASV Annual Meeting.

Further Reading

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June 2009