H1N1 INFLUENZA A VIRUS IN SWINE SUPPLEMENTAL RESEARCH PROGRAM
Location: Virus and Prion Research Unit
Title: Global coordination for swine influenza virus surveillance and research: what are we missing from the big picture?
Submitted to: American Association of Swine Veterinarians Annual Meeting
Publication Type: Proceedings
Publication Acceptance Date: November 30, 2011
Publication Date: March 10, 2012
Citation: Vincent, A.L., Kitikoon, P., Gauger, P.C., Gramer, M.R., Lorusso, A., Lager, K.M., Ciacci-Zanella, J.R. 2012. Global coordination for swine influenza virus surveillance and research: what are we missing from the big picture? In: Proceedings of the 43rd American Association of Swine Veterinarians Annual Meeting, March 10-13, 2012, Denver, Colorado. p. 507-512.
Surveillance for influenza A viruses (IAV) circulating in pigs and other non-human mammals has been chronically underfunded and virtually nonexistent in many areas of the world. This deficit continues in spite of our knowledge that influenza is a disease shared between man and pig from at least as far back as the 1918 Spanish Flu Pandemic. In March-April 2009, a novel pandemic H1N1 emerged in the human population in North America and demonstrated in a very public forum the paucity of data on influenza viruses in swine. This scrutiny continues. The gene constellation of the emerging virus was demonstrated to be a combination of genes from swine influenza A viruses (SIV) of North American and Eurasian lineages that had never before been identified in swine or other species. The emergent H1N1 quickly spread in the human population and the outbreak reached pandemic level 6 as declared by the World Health Organization on June 11, 2009. Although the 8 gene segments of the novel virus are similar to available sequences of corresponding genes from SIV from North America and Eurasia, no closely related ancestral IAV with this gene combination had been identified in North America or elsewhere in the world. Other than sporadic transmission to humans, swine influenza A viruses of the H1N1 subtype historically have been distinct from avian and other mammalian H1N1 influenza viruses in characteristics of host specificity, serologic cross-reactivity, and/or nucleotide sequence. The emergence of the 2009 pandemic H1N1 (pH1N1) virus brought a heightened awareness to the evolution and epidemiology of influenza A viruses in swine and presents a new era of challenges and opportunities for understanding and controlling influenza in pigs. Unfortunately, these opportunities have yet to be significantly realized in a better understanding of the ecology and evolution of IAV in swine, despite the passage of 2 years and investment of resources.
North American triple reassortant viruses
Swine influenza was first recognized in pigs in the Midwestern U.S. in 1918 as a respiratory disease that coincided with the human pandemic known as the Spanish flu. Since then, influenza has become an important disease to the swine industry throughout the world. The first influenza virus was isolated in 1930 by Shope and was demonstrated to cause respiratory disease in swine that was similar to human influenza. The classical swine lineage H1N1 (cH1N1) derived from the 1918 pandemic was relatively stable at the genetic and antigenic levels in U.S. swine for nearly 80 years.
The epidemiology of IAV in pigs dramatically changed after 1998 when triple reassortant viruses containing gene segments from the classical swine virus (NP, M, NS), human virus (PB1, HA, NA), and avian virus (PB2, PA) became successfully established in the pig population. The human lineage PB1, avian lineage PB2 and PA and swine lineage NP, M, and NS found in contemporary swine influenza viruses are referred to as the triple reassortant internal gene (TRIG) constellation. After their emergence, the H3N2 viruses reassorted with cH1N1 swine IAV. Reassortant H1 viruses are endemic with the H3N2 viruses in most major swine producing regions of the U.S. and Canada and since early in the new millennium, the vast majority of the fully characterized swine viruses contain the TRIG, regardless of subtype. Outside of North America, genetically related swine viruses that contain the TRIG have been identified in Korea, Vietnam, and China. Important to note, North American TRIG-containing swine viruses readily infect turkeys, which may play an unappreciated role in the epidemiology of SIV.
Since 2005, H1N1 and H1N2 viruses with the HA gene derived from human seasonal IAV emerged and spread across the U.S. in swine herds. The HAs from the human-like swine H1 viruses are genetically and antigenically distinct from classical swine lineage H1s. However, their TRIG genes are similar to those found in the TRIG cassette of the contemporary swine triple reassortant viruses. To represent the evolution of the currently circulating North American H1 viruses, a cluster classification has been established. Viruses from the classical H1N1 lineage-HA evolved to form alpha-, beta-, and gamma-clusters based on the genetic evolution of the HA gene; whereas H1 subtype isolates with HA genes most similar to human seasonal H1 viruses form the delta-cluster. All four HA gene cluster types can be found with neuraminidase genes of either the N1 or N2 subtype. The HA from the delta-cluster viruses were shown to have most likely emerged from at least two separate introductions of human seasonal HA from H1N2 and H1N1 viruses, are differentiated phylogenetically by two distinct sub-clusters, delta1 and delta2, respectively, and have undergone considerable genetic evolution in swine with some geographic distribution up to 2010. During the investigations of 2008-2010 viruses, the HAs of the delta-cluster were paired either with an N1 or N2 gene of human virus lineage but not of swine N1 lineage. Prior to 2009, the H1 SIV evolved by drift and shift while maintaining the TRIG backbone with the resulting viruses differing genetically and antigenically with obvious consequences for vaccine and diagnostic test efficacy.
Swine IAV with genetic lineages that are distinct from the North American TRIG viruses evolved in Europe and Asia. Although cH1N1 swine viruses previously circulated in Europe, Asia, and many other parts of the world, they were eventually replaced by a new lineage in Europe, a wholly avian H1N1 that emerged in 1979. The avian-lineage H1N1 was subsequently identified in Asia in 1993. Human-lineage H3N2 distinct from those in North America also emerged in Europe and Asia in the 1970s. Additionally, a human-like H1N2 emerged in pigs in Great Britain in the 1990s. A recent European surveillance study reported the continued circulation of the Eurasian avian-like H1N1, human-like H3N2 and human-like H1N2 in swine. All three subtypes were detected in Belgium, Italy and Spain, while only H1N1 and H1N2 viruses were found in UK and Northwestern France.
The epidemiology of influenza viruses in Asia should be particularly focused on China due to its high population density of swine, poultry, and wild waterfowl, along with its traditional husbandry and cultural practices. Contemporary viruses isolated from pigs in China are of North American and European virus lineages, reassortant viruses between the North American and European lineages, and reports of unique avian-lineage viruses. Recent publications from China document the presence of cH1N1, Eurasian H3N2, human-like H3N2, Eurasian H1N1, North American H3N2 and H1N2 containing the TRIG, pH1N1, and various reassortments between these genetic lineages. The majority of what is known about IAV in China is concentrated around Hong Kong and IAV in swine from much of the country remains relatively unknown. In South Korea, the cH1N1 and triple reassortant H1N2 and H3N2 co-circulate with an additional independent introduction of human-lineage H3N2. A similar human-lineage H3N2 with the North American TRIG was reported in Vietnam.
H1N1 and H3N2 have been reported in swine in Thailand since early 1980s. In general, the H3N2 and H1N1 SIVs circulating in Thai pigs are related to the lineages found in the Eurasian H3N2 and H1N1 viruses and cH1N1 respectively. Swine H3N2 viruses from early 2000 to 2007 contain human lineage HA and NA genes with internal genes from the Eurasian (PB1, PB2, PA and M genes) and cH1N1 (NP and NS genes) swine lineages. The Thai swine H1N1 viruses (ThH1N1) from 2000 until the emergence of the pH1N1 virus in 2009 are unique hybrids of classical-swine and Eurasian-swine lineage. These H1N1 viruses could be grouped into classical-HA and Eurasian-NA swine lineage with internal genes either being all Eurasian swine (7+1) or all Eurasian swine except for classica