Spillovers and H5N1 HPAI

  In his 2012 book, Spillover, author David Quammen paints a vivid picture of the growing pandemic risk facing humanity^[1]. In gripping detail, he guides the reader through a crash course on epidemiology, with a focus on zoonotic diseases (those which are transmitted from animals to humans, or vice-versa). A spillover event occurs when a pathogen that is typically transmitted between non-human animal hosts "spills over," causing novel infection in a human population. Nascent infections in an immunologically-naive population tend to be highly virulent and cause greater degrees of morbidity and mortality. Recent examples of spillover events include the 2014 Ebola pandemic, the 2020 COVID-19 pandemic, and the recent human case of H5N1 influenza acquired from exposure to infected cattle in Texas.

H5N1, or Highly Pathogenic Avian Influenza (HPAI), is a subtype of influenza that commonly circulates in birds and poultry. Transmission of the virus from birds to cows might itself be considered a spillover event, as the virus adapted to a new mammalian host. This was first reported on March 25, 2024 ^[2]. The first human case of cattle-acquired H5N1 was reported just a few days later. (Previous human infections of H5N1 from other exposure sources have been documented, and sporadic cases of mammalian infection have been observed in sea lions and foxes.)

HPAI provides a great example of understanding the concept of spillover in real-time. Let's consider this in the sense of two broad factors: 1) the characteristics of the pathogen and hosts; and 2) human activity - our social/cultural practices.

H5N1 is a single-stranded, segmented, negative-sense RNA virus with a specific host set consisting of migratory waterfowl and poultry. In these hosts, the influenza virus is enzootic - it circulates widely and evolves within the host populations that act like a massive "mixing vessel." The migratory waterfowl hosts also carry the virus across a wide geographic range, and incidental contact with other animal species may result in sporadic spillover events (Fig 1).

Fig. 1. Formation of 2 representatives of avian influenza (H5N1) virus from China ^[3]

As influenza viruses move through their host populations, they accumulate point mutations as a natural part of the replication process. The gradual change in viral characteristics emerging from this process is called antigenic drift. When differing subtypes of influenza encounter each other - like when infected migratory ducks encounter infected herds of swine - influenza viruses can exchange entire segments of their DNA. This process is called reassortment, and it can result in new, radically-different viral subtypes, which we refer to as antigenic shift. The latter can exhibit greater pandemic potential, as new host populations have immune naivety to the novel forms of virus.

The characteristics of "drift and shift" make influenza particularly dangerous as potential spillover cause of epidemics and pandemics. Indeed, the H1N1A "Great Influenza" pandemic of 1918 was one of the deadliest plagues in human history, responsible for up to 50 million deaths globally. The high degree of variation exhibited by influenza and its ability to change with unpredictable rapidity make it particularly difficult to protect against. Seasonal vaccines must be prepared nearly a year in advance and are formulated from best estimates of strains that scientists believe are most likely to be in circulation for the coming flu seasons. The search for a universal flu vaccine that would confer lasting protection against all H/N subtypes remains elusive.

Human activity also contributes to the likelihood of spillover events. Just as avian hosts bring viruses into contact with other animal populations through their geographic migration paths, so do humans. We travel the globe, we interact in massive population centers, and we expand our territories. We also significantly alter our environment, through land-use expansion, slash-and-burn, urban development, animal husbandry and breeding, and anthropogenic climate change.

While development increases the chances of human exposure to "neglected" or less-encountered pathogens (as was the case with Ebola), it can also generate conditions that help viruses and bacteria thrive. Industrial farming is the quintessential example: over-crowding leads to stressful, unsanitary conditions where animals are continually infected and circulating pathogens readily evolve through massive populations of confined, close-contact hosts. Ideal incubators. Human farm workers are incidental hosts - potential spillover points - as they routinely interact with these infected animal populations ^[5].

Human activities don't merely create or amplify the conditions for zoonotic exposure, but can also serve to undermine public health efforts to surveil, prevent, and mitigate spillover events. As Dr. Gounder aptly notes, the farming industry largely relies upon migrant and undocumented workers ^[6]. These workers, already facing safety risks from inadequate PPE and lack of regulatory oversight, are less likely to report concerns or symptoms out of fear for retaliation. Well-intentioned public health workers may be perceived as part of a nebulous government apparatus that is to be mistrusted or avoided entirely. Even if workers are willing to report concerns over working conditions or illness, there are still communication barriers, with many workers speaking only native languages that are not frequently spoken in the U.S., such as K'iche'^[6].

Fig. 2. Zippia data on non-English language frequency of dairy workers

Social relationships between the public, industry, providers, and government can also shape the occurrence and magnitude of spillover events. The COVID-19 pandemic laid bare the contentious struggle between conflicting attitudes of protectionism, personal liberty, and how we as a society balance personal versus public interest. Perceived failures in prevention and mitigation, vaccine skepticism, and general mistrust of officials and policy can potentially exacerbate the next spillover event, as public will to enact PH interventions relies upon the belief that such actions are effective, beneficial, and not unreasonably onerous. Mistrust has grown immensely since the COVID-19 pandemic (Fig. 3).

The threat of increased spillover events and subsequent zoonotic epidemics is a clear and present danger for humanity. Epidemiologists have been sounding the alarm for decades. Popular authors like David Quammen and Laurie Garret have presented the same warnings to a broader audience. The pandemics of the last century should have drilled the message home. And yet, we humans have very short memories. Time has a way of making us complacent in the face of ongoing threats. Nowhere is this more apparent than when it comes to public health infrastructure and funding (a topic for future posts). So the years go by. We forget, or we simply no longer care. SARS-CoV-2 becomes, to the cynic, "just a common cold." The new flu is "no big deal." We go about our business as usual, undeterred and asleep at the wheel, sowing the seeds for the next major spillover.

References

1. Quammen, David (2012). Spillover: Animal Infections and the Next Human Pandemic. https://a.co/d/5j33FVf
2. Centers for Disease Control (2024). Current H5N1 Bird Flu Situation in Dairy Cows. https://www.cdc.gov/flu/avianflu/mammals.htm#:~:text=A%20multi%2Dstate%20outbreak%20of,viruses%20were%20found%20in%20cattle.
3. Tian, et al. (2023). Highly Pathogenic Avian Influenza Virus (H5N1) Clade 2.3.4.4b Introduced by Wild Birds, China, 2021. Emerging Infectious Diseases 29(7):1367-1375 (https://www.researchgate.net/publication/371973833_Highly_Pathogenic_Avian_Influenza_Virus_H5N1_Clade_2344b_Introduced_by_Wild_Birds_China_2021
4. Science Direct (2024). Antigenic Drift. https://www.sciencedirect.com/topics/immunology-and-microbiology/antigenic-drift
5. MSPCA (2024). How Factory Farming Could Create the Next Pandemic. https://www.mspca.org/animal_protection/factory-farming-pandemic/
6. Gounder, Céline (2024). H5N1 doesn’t have to be a repeat of Covid-19’s ‘public health versus the economy’. https://www.statnews.com/2024/05/17/h5n1-bird-flu-do-not-repeat-covid-19-public-health-versus-economy-battle/
7. Jain, Sanjula (2023). The COVID-19 Pandemic Amplified Feelings of Mistrust in and Frustration with the U.S. Healthcare System. https://www.trillianthealth.com/insights/the-compass/the-covid-19-pandemic-amplified-feelings-of-mistrust-in-and-frustration-with-the-u.s.-healthcare-system