Hindsight 20/20: What have we learned about influenza A viruses in pigs and people since the 2009 H1N1 pandemic?

Introduction

Influenza A viruses (IAV) are the causative agents of one of the most important viral respiratory diseases in pigs and humans. Human and swine IAV are prone to interspecies transmission, leading to regular incursions from human to pig and vice versa. This bidirectional transmission of IAV has heavily influenced the evolutionary history of IAV in both species. Interspecies transmission of distinct human seasonal lineages, adaptation followed by sustained and intense within-host transmission, virus migration through live pig transport and trade, and rapid evolution represent a considerable challenge for pig health and production. Although only subtypes of H1N1, H1N2, and H3N2 are endemic in swine around the world, considerable genetic and antigenic diversity can be found in the hemagglutinin (HA) and neuraminidase (NA) genes, as well as the remaining 6 genes. The risk of this pattern, regular human seasonal IAV incursion and IAV evolution in swine, to the human population was brought to the forefront during the 2009 H1N1 human pandemic. The complicated global epidemiology of IAV in swine and the implications for public health and influenza pandemic planning are entangled and will be reviewed in the presentation.

Swine IAV was historically characterized as a seasonal respiratory disease, primarily in weaned pigs with waning maternal immunity. Today, clinical disease in the USA peaks during times of the year associated with fluctuations in temperature and decreased ventilation, similar to the human influenza season (Janke 2013). In US pigs, a primary peak is observed in November-December with a secondary spike in March-April (Walia et al. 2019), with a similar trend in Canada (Poljak et al. 2014). However, contemporary influenza illness and diagnosis can be found at any time of the year (Zeller et al. 2018) in nearly all age groups of pigs, even suckling pigs from sows with high titers of influenza specific serum antibodies (Allerson et al. 2013; Corzo et al. 2014).

Human-swine IAV dynamics

The extraordinary genetic and antigenic diversity of H1 and H3 swine IAV is arguably the greatest challenge to controlling infection and to the development of broadly effective vaccines for swine and for human pandemic preparedness. Further, there remains a paucity of contemporary swine IAV sequence and epidemiologic data in most geographic regions. There is sustained transmission of three main lineages of H1 (Figure 1A) and multiple lineages of H3 from human seasonal IAV established across several decades in global pig populations (Figure 1B), with approximately 30 contemporary well-supported monophyletic HA gene clades in swine. Throughout the history of IAV in swine, incursions of human seasonal IAV have had the most dramatic impact on the evolution of IAV in swine. Following the spread of the 2009 H1N1 swine-origin pandemic (H1N1pdm09) in humans, annual introduction of this human seasonal H1N1 virus into pigs has potentiated a decade of reassortment and diversification of HA, NA, and the other 6 genes in endemic swine lineages (Nelson et al. 2015; Gao et al. 2017; Rajao et al. 2017; Rajao et al. 2018). This diversity has important implications for both swine health and control of IAV using vaccines, and is a challenge for pandemic preparedness for the global public health community.

The diversity of swine IAV globally and the realized human-swine interface is incredibly important in the context of zoonotic IAV infections in humans (called “variants” to distinguish from human seasonal IAV). Antigenically-variable and novel swine viruses pose a threat to humans if human population immunity no longer recognizes the resultant swine lineages, as was dramatically demonstrated by the H1N1pdm09. Significant increases in the detection of variant IAV infections in people began with H3N2 swine IAV in the USA in 2012 (Epperson et al. 2013), particularly swine IAV that have reassorted with H1N1pdm09. Variant cases are regularly reported in the USA (Choi et al. 2015; Greenbaum et al. 2015; Duwell et al. 2018; Pulit-Penaloza et al. 2018) and in other countries (Piralla et al. 2015; Resende et al. 2017; Xie et al. 2018; Lu et al. 2019). The risk of variant infection is likely dependent on animal production systems which might differ in the relative degree of human-pig exposure, the type of animal-human interface (e.g., live animal markets, exhibition practices), the ecology of the virus, and other less tangible factors (Karesh et al. 2012). However, many phylogenetic clades of swine IAV currently circulate without evidence of human transmission or variant cases.

Without the ability to accurately predict which of the 30 current clades of swine IAV may cause variant infections or even pandemics, human vaccine preparedness efforts for swine strains are difficult. The global genetic diversity of swine IAV circulating from 2016 to present and of swine IAV in the USA over the past 6 months demonstrated that most swine IAV were significantly different from the current H1 and H3 components of human IAV vaccines (Anderson et al. 2020). Few of the genetic clades globally detected in swine currently contain a WHO pandemic-preparedness Candidate Vaccine Virus (CVV) and those CVVs that are available might not provide protection given observed genetic and antigenic differences in circulating swine viruses. Since human and swine IAV evolution are inherently tangled, a system to regularly and rapidly prioritize and evaluate evolving swine IAV in the context of human risk should be part of a comprehensive pandemic preparedness plan. A more systematic analysis of swine IAV as a risk to the human population is a priority of the OIE and FAO influenza network (OFFLU). Robust surveillance in swine is a critical component in this effort, with priority given to geographic areas with high levels of swine IAV diversity, rapid evolution, production practices that support viral transmission and migration, and specific animal-human interfaces that promote greater contact between pigs and people. Efforts to antigenically characterize swine IAV through an OFFLU report occur biannually at the WHO Vaccine Composition Meeting, where animal influenza activity data are presented concurrently with human seasonal influenza activity data. If the activity of a particular animal IAV clade is high, variant cases are identified, and/or genetic and antigenic diversity of that clade is significantly drifted from previously recommended pre-pandemic CVVs and current human seasonal vaccine strains, a representative strain may be considered for development of a new CVV. The CVVs are shared among the WHO Global Influenza Surveillance and Response Network (GISRS) and with academic, governmental, and industry partners for research or commercial development (Robertson et al. 2011). Prior to the 2009 pandemic, CVVs were exclusively of avian origin, but more recently, several variant viruses have been selected based on confirmed swine-origin variant infections and antigenic divergence from other CVVs and seasonal vaccines. To make this determination, the crossreactivities of newly detected swine viruses are tested against monovalent ferret antisera raised against CVVs and/or seasonal vaccine strains and, when available, sera from seasonal influenza vaccinated or exposed humans. To further characterize the antigenic relationships between swine and human IAV, comprehensive temporal antigenic characterization of swine and human seasonal vaccine strains has also been undertaken and will be discussed.

Figure 1. Phylogeny of contemporary swine H1 (A) and H3 (B) influenza A virus hemagglutinin genetic lineages, demonstrating 30 genetically distinct clades that globally co-circulate.

Phylogeny of contemporary swine H1 (A) and H3 (B) influenza A virus hemagglutinin genetic lineages, demonstrating 30 genetically distinct clades that globally co-circulate.

Conclusions

IAV in swine is highly diverse, with sustained transmission in global pig populations of at least 30 genetic clades. The NA and other 6 gene segments also demonstrate a high degree of diversity. Most swine IAV were significantly different at the genetic level from the current H1 and H3 components of human IAV vaccines. Only approximately 1/3 of the 30 distinct genetic clades detected in swine globally currently contain a CVV or human seasonal vaccine, and the degree to which those CVVs provide protection is uncertain given observed genetic and antigenic differences identified in recently circulating swine viruses. Since human and swine IAV evolution are inherently tangled, a system to regularly and rapidly prioritize and evaluate evolving swine IAV in the context of human risk should be part of a comprehensive pandemic preparedness plan. Surveillance in swine must continue to be a priority for animal and public health, with priority given to geographic areas with high levels of swine IAV diversity, rapid evolution, production practices that support viral transmission and migration, as well as specific animal-human interfaces that promote greater contact between pigs and people.

Published in the proceedings of the International Pig Veterinary Society Congress – IPVS2020. For information on the event, past and future editions, check out https://ipvs2022.com/en.

Hindsight 20/20: What have we learned about influenza A viruses in pigs and people since the 2009 H1N1 pandemic?

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