A Tale of Two Species—Influenza Virus Diversity in Swine and People

Lewis, NS, et al. The global antigenic diversity of swine influenza A viruses. Elife. (2016).

A collaborative project from several Centers of Excellence for Influenza Research and Surveillance (CEIRS) highlights the complex and ever-evolving relationship between influenza and its many hosts. In their recent publication, Dr. Nicola S. Lewis, from the Center for Research on Influenza Pathogenesis (CRIP), and colleagues from around the globe perform the most comprehensive analysis of swine influenza virus antigenicity to date, revealing areas for further investigation and potential risks to human and animal health. The embedded video from Cambridge TV features an interview with Dr. Lewis. We expanded on several points from this interview in our feature article below.

See this short video courtesy of Cambridge TV featuring Dr. Lewis.

Keeping pace with influenza viruses in pigs and people

Influenza virus infection and vaccination arm the immune system, allowing it to recognize and defend against closely related viruses. Mounting a lasting protective response relies upon immune cells to memorize viral features after exposure. The major glycoproteins of influenza viruses, hemagglutinin and neuraminidase, protrude from the virus surface and make contact with human cells in the respiratory tract during infection. The immune system learns to recognize these viral proteins, unlike any in the human body, and makes targeted antibodies preventing further illness if ever re-exposed. However, influenza viruses have evolved to evade this response. They do so by progressively altering their surface proteins so that eventually they are no longer recognized by antibodies made against older viruses. This places the flu and its hosts in a coordinated race, with the virus seemingly one step ahead.

In addition to the significant impact on human health, influenza viruses present a considerable challenge to agricultural animals like swine. Despite its importance for host susceptibility and effective vaccine use, relatively little is known about the antigenic diversity of influenza viruses in pigs. Lewis et al. performed a comprehensive analysis of the global antigenic diversity of H1 and H3 human and swine influenza viruses spanning from 1930 to present day. The authors characterized the antigenicity of almost 600 viruses by comparing how well antibodies against one virus recognized others. Compared to human viruses, the antigenic diversity of circulating influenza viruses in pigs is vast, even though the antibody-evading properties of influenza viruses in swine populations evolve much slower. While human viruses race ahead, evolving together, swine viruses evolve in segregated patterns that are initiated with relatively frequent independent introductions of human seasonal strains, expanding the global diversity of the flu in pigs. This poses a challenge to protection against the flu in pig farms. Vaccines against one strain are unlikely to be protective against the wide diversity of influenza viruses pigs may encounter. The results of the Lewis et al. study may eventually inform the development of better vaccines by combining the antigenic diversity of viruses in a region with epidemiology and agricultural practices.

The transmission of viruses between humans and pigs is a two-way street. This study confirmed that over time humans routinely serve as an infection source for new influenza viruses in pigs, explaining the many different strains of flu identified. Due to the independent antigenic change specific to each swine population, viruses introduced from humans into pig populations many years ago, such as the seasonal H1, 1970s H3, and 1990s H3 viruses, are no longer similar to viruses found in humans now. This leaves younger human populations, never exposed to human influenza viruses of the past, at risk. Analysis of the antigenic diversity of local swine viruses and human population characteristics may help identify swine viruses with the potential to infect humans.

Comparisons of antigenicity around the world also revealed interesting trends. The authors found that the diversity of influenza viruses in the United States is greater than that observed in Europe. Understanding the basis for these differences is complex and multifactorial. It is likely tied to viral genetics and agricultural practices that include geographical movement, vaccine use, age, and synchronicity of pig production cycles. Importantly, a combination of viral traits, including receptor binding and resistance to inflammatory responses, allows for effective spread within and between hosts. More research is needed to tease apart the complex relationship between influenza and its many hosts.

Diverse expertise and strength in numbers

The DPCC communications team interviewed Dr. Lewis to hear more about this study and the virtues of collaborative cross-sector, international science. Dr. Lewis emphasized, “the more cross-cutting sector approaches used, the better.” Just after the pandemic in 2009, they started a collaborative swine project with Dr. Amy Vincent, also from CRIP. The team studied the antigenic differences of H1N1 and H1N2 viruses in pigs in the United States and revealed critical gaps in what was known about the evolution of influenza viruses in this species. This initial study spurred this work on the global diversity of swine viruses. Lewis and Vincent drew collaborators into the project from the OIE and FAO Network of Expertise on Animal Influenza (OFFLU) swine influenza working group, as well as other investigators from the St. Jude CEIRS (SJCEIRS) and CRIP. Members of this multidisciplinary team collectively formed an international swine influenza research team that grew as people began to share data.

While the publication highlights important findings, this collaboration is ongoing. Additional work is needed to understand the impact and importance of antigenic diversity in swine on human and animal health. Sustained longitudinal funding remains the biggest obstacle as collaborators across the globe differ in the level of resources available. The CEIRS Network is critical for surveillance efforts, but some gaps remain due to limited funds and regional politics resulting in geographical biases. The team hopes to make data more inclusive moving forward, expanding surveillance into under-represented areas such as Southeast Asia, China, Oceania and Latin America.

This type of collaborative research is no small feat, but enjoyable and well worth the effort concludes Dr. Lewis. “The CEIRS Network gave a framework for how these types of collaboration would work,” said Dr. Lewis, emphasizing the importance of sharing data and reagents worldwide.  Importantly, this project was founded on strong scientific inquiry and enthusiasm for an area critical for animal and human health.

Evolving research and surveillance

Dr. Lewis is not new to influenza, having worked extensively on equine influenza viruses. Circulating horse influenza viruses evolve similarly as those found in humans and pigs, but at an even slower rate. “There is a lot to learn from other influenza host systems,” said Dr. Lewis. The current project puts this concept in sharp focus—where all hosts, pigs and humans alike, play a role in viral evolution. Understanding the biology, diversity and evolution of influenza viruses in different hosts reveals commonalities in the fundamental biology of influenza, something that benefits from cross-sector, interdisciplinary collaboration.

The implications of this study provide a baseline from which to identify swine viruses with epidemic or pandemic potential, identify at-risk susceptible human populations, and inform agricultural practices. Based on these results, a collaborative CEIRS project to systematically evaluate the antigenic relationships between swine viruses identified from surveillance studies and human seasonal viruses was initiated in 2016.  Continued research and surveillance are needed, particularly in underrepresented areas of the world. This study provides a basis for further examination of the underlying biology driving influenza diversity at the genetic and antigenic levels across species.

16 April 2013, Rome - Group Photo, SIV Group Meeting, Nigeria room, FAO Headquarters.

Image of Keith Hamilton, Bundit Nuansrichy, Tung Nguyen, Takehiko Saito, Ariel Pereda, John Pasick, Janice Zanella, Richard Webby, Nicola Lewis, Frank Wong, Sabrina Swenson, Gwen Dauphin (top row), Ruben Donis, Ian Brown, Amy Vincent, Kristien Van Reeth, Elizabeth Mumford, Gounalan Pavade (bottom row), several of the co-authors on the eLife publication and collaborators on OFFLU swine influenza virus group.