Continual Reintroduction of Human Pandemic H1N1 Influenza A Viruses into Swine in the United States, 2009 to 2014

Abstract

The diversity of influenza A viruses in swine (swIAVs) presents an important pandemic threat. Knowledge of the human-swine interface is particularly important for understanding how viruses with pandemic potential evolve in swine hosts. Through phylogenetic analysis of contemporary swIAVs in the United States, we demonstrate that human-to-swine transmission of pandemic H1N1 (pH1N1) viruses has occurred continuously in the years following the 2009 H1N1 pandemic and has been an important contributor to the genetic diversity of U.S. swIAVs. Although pandemic H1 and N1 segments had been largely removed from the U.S. swine population by 2013 via reassortment with other swIAVs, these antigens reemerged following multiple human-to-swine transmission events during the 2013-2014 seasonal epidemic. These findings indicate that the six internal gene segments from pH1N1 viruses are likely to be sustained long term in the U.S. swine population, with periodic reemergence of pandemic hemagglutinin (HA) and neuraminidase (NA) segments in association with seasonal pH1N1 epidemics in humans. Vaccinating U.S. swine workers may reduce infection of both humans and swine and in turn limit the role of humans as sources of influenza virus diversity in pigs.

Importance: Swine are important hosts in the evolution of influenza A viruses with pandemic potential. Here, we analyze influenza virus sequence data generated by the U.S. Department of Agriculture's national surveillance system to identify the central role of humans in the reemergence of pandemic H1N1 (pH1N1) influenza viruses in U.S. swine herds in 2014. These findings emphasize the important role of humans as continuous sources of influenza virus diversity in swine and indicate that influenza viruses with pandemic HA and NA segments are likely to continue to reemerge in U.S. swine in association with seasonal pH1N1 epidemics in humans.

FIG 1

Phylogenetic relationships between pandemic H1 segments. The time-scaled Bayesian MCC tree was inferred for the HA (H1) sequences of 933 viruses collected from swine and humans in the United States from 2009 to 2014, including 173 viruses from swine and 760 viruses from humans. The branches are color coded by host and time (U.S. influenza epidemic) of collection (September to August). sw09-10, swine viruses collected during the 2009-2010 epidemic; sw10-11, swine viruses collected during the 2010-2011 epidemic; sw11-12, swine viruses collected during the 2011-2012 epidemic; sw12-13, swine viruses collected during the 2012-2013 epidemic; sw13-14, swine viruses collected during the 2013-2014 epidemic. The clade of human viruses from the 2013-2014 epidemic is highlighted in the box shaded orange. Posterior probabilities of >0.90 are provided for key nodes. An identical phylogeny with tip strain name labels is provided in Fig. S2 in the supplemental material.

FIG 2

Heat map of virus transmission between humans and swine. Markov jump counts measure the number of inferred location state transitions, modeled by a continuous-time Markov chain process, that occur along the branches of the phylogeny. The intensity of the color (red, high; white, low) reflects the number of Markov jump counts between one temporally defined host population (y axis) and another (x axis), which have been abbreviated (e.g., hu08-09, viruses collected in humans during the 2008-2009 epidemic; sw08-09, swine viruses collected during the 2008-2009 epidemic). The results are presented separately for the NA (a) and NP (b) segments. For clarity, each heat map has been divided into four quadrants that represent linkages between human viruses from a seasonal epidemic and human viruses from a different (usually preceding) epidemic (i.e., human-to-human transmission) (I), linkages between swine viruses from a seasonal epidemic and human viruses from a different (usually preceding) epidemic (i.e., human-to-swine transmission) (II), linkages between human viruses and swine viruses (i.e., swine-to-human transmission) (III), and linkages between swine viruses and swine viruses from a different (usually preceding) epidemic (i.e., swine-to-swine transmission) (IV).

FIG 3

Numbers of viruses with each of the eight pandemic segments. Of 444 viruses with whole-genome sequences (not including fair pigs or viruses with all eight segments of pandemic origin), the numbers that contain PB2, PB1, PA, HA, NP, NA, MP, and NS segments of pandemic origin are shown. The frequency of each segment indicates the extent of reassortment and onward maintenance of the pH1N1 internal genes in U.S. swine, with the loss of the HA and NA genes outside wholly pandemic viruses.

FIG 4

Association between human-to-swine virus transmission and pH1N1 activity in humans. (a) Proportion of total influenza virus specimens that were positive for pH1N1 virus calculated for each week from the beginning of the pandemic in the United States (week 35 of 2009) to the most recent report (week 39 of 2014), as reported by CDC FluView (http://www.cdc.gov/flu/weekly). (b) Heat map of the number of Markov jump counts between one temporally defined host population (y axis) and another (x axis). The labeling of the heat map is similar to that in Fig. 2 except that, for simplicity, all human viruses from 2009 to 2014 were consolidated into a single category, “human.”