#18,000
While governments and agencies are quick to reassure that HPAI H5 poses only a low risk to public health - which appears to be true, at least for the time being - a lot of experts are legitimately worried by the unprecedented moves the virus has made over the past 3 years.
A lot of that concern stems from our lack of surveillance and testing. It is hard to quantify a risk when countries aren't aggressively monitoring the virus, and then sharing that information.
The default position of many governments and agencies is to deny that a novel virus poses a specific threat, until there is definitive proof that it does.
Hence, it took weeks before China admitted SARS-CoV-2 could transmit from human-to-human, and the debate raged globally for months over COVID's ability to reinfect individuals, or to spread via aerosols (yes, on both counts).
Since cows have been long assumed to be at low risk for avian flu infection (despite previous studies suggesting otherwise), sick dairy cows in Texas went untested for the HPAI virus for several weeks after they began falling ill last January.
Even today, beeves (adult cattle used for food) aren't being routinely tested for HPAI, and only limited testing of `symptomatic' dairy cows is currently recommended (see USDA Testing Recommendations for Influenza A in Cattle).
Testing of other vulnerable livestock, including goats and pigs, appears similarly constrained, despite repeated warnings on the risks of the virus getting into swine herds (see EID Journal: Divergent Pathogenesis and Transmission of Highly Pathogenic Avian Influenza A(H5N1) in Swine).
To be fair, there are limited resources available for testing, and literally tens of millions of heads of potentially vulnerable livestock in this country. There are rules, frameworks, and a myriad of legal precedents under which agencies must work, and bureaucratic change often comes slowly.
While it remains unknown whether HPAI H5 will ever pose a pandemic threat, its evolving threat may be rapidly outstripping our ability to cope.
All of which brings us to a cautionary report from the American Journal of Veterinary Research, which goes into the history of HPAI (and LPAI) viruses, and examines the risks posed by increasing spillovers into mammalian species (including pigs).
The virus is out of the barn: the emergence of HPAI as a pathogen of avian and mammalian wildlife around the globe
Jonathan A. Runstadler DVM, PhD jonathan.runstadler@tufts.edu and Wendy B. Puryear PhD
DOI: https://doi.org/10.2460/ajvr.24.01.0018
Volume/Issue: Online Early
Online Publication Date: 13 Apr 2024
Open access
Abstract
Highly pathogenic avian influenza (HPAI) has persisted as a One Health threat whose current circulation and impact are addressed in the companion Currents in One Health by Puryear and Runstadler, JAVMA, March 2024. Highly pathogenic avian influenza emerged as a by-product of agricultural practices and adapted to endemic circulation in wild bird species.Over more than 20 years, continued evolution in a complex ecology involving multiple hosts has produced a lineage that expanded globally over the last 2 years. Understanding the continued evolution and movement of HPAI relies on understanding how the virus is infecting different hosts in different contexts.This includes understanding the environmental factors and the natural ecology of viral transmission that impact host exposure and ultimately evolutionary trajectories. Particularly with the rapid host expansion, increased spillover to mammalian hosts, and novel clinical phenotypes in infected hosts, despite progress in understanding the impact of specific mutations to HPAI viruses that are associated with spillover potential, the threat to public health is poorly understood.Active research is focusing on new approaches to understanding the relationship of viral genotype to phenotype and the implementation of research and surveillance pipelines to make sense of the enormous potential for diverse HPAI viruses to emerge from wild reservoirs amid global circulation.
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Mammalian Adaptation
The level of concern remains very high for transmission of HPAIv into agricultural poultry operations and much debate continues about the merits and pitfalls of vaccination and management strategies to prevent this.8 However, from the veterinary and human medicine standpoint, one of the most critical aspects being tracked is the spillover of current HPAI circulation into mammalian hosts and adaptation that may be associated with that spillover and onward transmission.
Since January of 2023, several characteristics of this spillover have heightened concerns but require more research to understand. The first is the sheer number of animals and species in which spillover infection has been documented.25,28 The 2.3.4.4b viral lineage appears to infect multiple bird species more commonly than it has previously. Among these are a variety of raptors whose illness has proved highly visible due to their charismatic nature and the efforts of multiple groups that respond to rescue and release injured and ill raptors back to the natural environment. However, in addition to raptors, many mammalian hosts have had infections with severe clinical signs, primarily neurologic, and death as a result.25,29
Intermediate Host versus Direct Transmission
For a long time, the influenza research community has understood the role of intermediate hosts, such as swine, in introducing epidemic strains to human populations.30,31 Host tropism is governed in part by the ability of the HA molecule to bind sialic acid residues on host cell glycoproteins decorating the exterior surface of epidermal cells that become infected in the respiratory and gastrointestinal tracts.However, each host produces glycoproteins that are expressed on the exterior of the host cells in slightly different ways in different tissues. As a result, many LPAI circulating in the wild only bind well to cells of their primary host, for instance, avian cells, and not those of other animal hosts. Pigs, however, seem adept at hosting both some avian influenza strains and some human strains of influenza, which allows these hosts to serve as potential “intermediates” where mixing and reassortment of viral segments can result in a new virus better adapted to human infection but of a novel antigenicity more prone to epidemic spread and not covered by current vaccination from seasonal strains (Figure 2).In an alternative scenario for an intermediate host, another mammal’s ability to host avian viruses can also provide time for additional mammalian-specific mutations or reassortment to be selected that predisposes the virus to further spillover and host expansion. It is believed this may explain some canine infections with influenza, as an example.32
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Conclusions
The current circulation of evolving lineages of HPAIv is challenging our understanding and assessment of the threat of this virus in a One Health context. Novel neurogenic phenotypes in novel hosts, increased frequency of spillover into mammalian hosts, and an ever-expanding diversity of H5Nx viral genotypes circulating in animal reservoirs in new ecosystems have demonstrated the limitations of current understanding.
Research is focused on understanding the potential of viruses to spill over through (1) better understanding of virus ecology in diverse hosts, and (2) characterizing the relationship between viral genotype and viral phenotype in a diverse background.
Breakthroughs that will help predict and limit the impact of HPAI on animals, humans, and the environment will depend on the implementation of new approaches to characterize global diversity through analysis pipelines that use computational models and machine learning, high-throughput in vitro phenotyping, and limited in vivo experiments to assess HPAI.
Although we've stood on the precipice before with H5N1 (see here, here, and here), only to have the threat recede, this time `feels' different. We are dealing with far more genotypes of the virus than we've ever seen before, and a very nearly global spread of the virus.
While human cases remain reassuringly low, the number of mammalian species being infected continues to rise.
We could get lucky, and H5N1 fizzles. But even if we do, nature has a toolbox full of other novel flu subtypes with which to tinker. At some point our luck will run out.
Anything we can learn now about how H5N1 is spreading in mammals can only help us in the future.
